P53
Encyclopedia
p53 is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organism
s, where it regulates the cell cycle
and, thus, functions as a tumor suppressor that is involved in preventing cancer
. As such, p53 has been described as "the guardian of the genome
", the "guardian angel gene", and the "master watchman", referring to its role in conserving stability by preventing genome mutation.
The name p53 is in reference to its apparent molecular mass
: It runs as a 53-kilodalton (kDa) protein on SDS-PAGE
. But, based on calculations from its amino acid
residues, p53's mass is actually only 43.7 kDa. This difference is due to the high number of proline
residues in the protein, which slow its migration on SDS-PAGE
, thus making it appear heavier than it actually is. This effect is observed with p53 from a variety of species, including humans, rodents, frogs, and fish.
(17p13.1). The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb.The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53. TP53 orthologs have been identified in most mammals for which complete genome data are available.
In humans, a common polymorphism
involves the substitution of an arginine
for a proline
at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility, however, a combined analysis did not show a link.
For these mammals, the gene is located on different chromosomes:
(Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.)
s long and has seven domains:
A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53.
KO mutations
and position for p53 interaction with TFIID are listed below:
9aaTADs mediate p53 interaction with general coactivators - TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA).
Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore OD mutations have a dominant negative effect on the function of p53.
Wild-type p53 is a labile protein
, comprising folded and unstructured regions
that function in a synergistic manner.
. In its anti-cancer role, p53 works through several mechanisms:
Activated p53 binds DNA and activates expression of several genes including WAF1/CIP1 encoding for p21
. p21 (WAF1) binds to the G1
-S
/CDK
(CDK2) and S/CDK complexes (molecules important for the G1/S transition
in the cell cycle) inhibiting their activity.
When p21(WAF1) is complexed with CDK2 the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Thus, cells will divide uncontrollably, and form tumors.
Recent research has also linked the p53 and RB1
pathways, via p14ARF, raising the possibility that the pathways may regulate each other.
p53 by regulating LIF
has been shown to facilitate implantation in the mouse model and possibly in humans.
p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning
.
, IR
, or chemical agents such as hydrogen peroxide), oxidative stress
, osmotic shock
, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change
forces p53 to be activated as a transcription regulator
in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.
The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM
, CHK1 and CHK2, DNA-PK, CAK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF
.
In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2
(also called HDM2 in humans), which is itself a product of p53, binds to p53, preventing its action and transports it from the nucleus
to the cytosol
. Also Mdm2 acts as ubiquitin ligase
and covalently attaches ubiquitin
to p53 and thus marks p53 for degradation by the proteasome
. However, ubiquitylation of p53 is reversible. A ubiquitin specific protease, USP7
(or HAUSP
), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation. This is one means by which p53 is stabilized in response to oncogenic insults.
Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300
or PCAF
, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7
, can deacetylate p53, leading to an inhibition of apoptosis. Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.
If the TP53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disease known as Li-Fraumeni syndrome
. The TP53 gene can also be damaged in cells by mutagen
s (chemicals
, radiation
, or virus
es), increasing the likelihood that the cell will begin decontrolled division. More than 50 percent of human
tumor
s contain a mutation
or deletion
of the TP53 gene. Increasing the amount of p53, which may initially seem a good way to treat tumors or prevent them from spreading, is in actuality not a usable method of treatment, since it can cause premature aging. However, restoring endogenous
p53 function holds a lot of promise. Loss of p53 creates genomic instability that most often results in the aneuploidy
phenotype.
Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus
(HPV), encodes a protein, E6, which binds the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, pRb
, by the HPV protein E7, allows for repeated cell division manifested in the clinical disease of wart
s. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix
over the years can cause irreversible changes leading to carcinoma in situ
and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.
In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop, MDM2 is itself induced by the p53 protein. However, mutant p53 proteins often do not induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels.
, David P. Lane
, Arnold Levine, and Lloyd Old
, working at Imperial Cancer Research Fund (UK) Princeton University
/UMDNJ (Cancer Institute of New Jersey), and Sloan-Kettering Memorial Hospital, respectively. It had been hypothesized to exist before as the target of the SV40
virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences
in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science
). The human TP53 gene was cloned in 1984 and the full length clone in 1985.
It was initially presumed to be an oncogene
due to the use of mutated cDNA following purification of tumour cell mRNA. Its character as a tumor suppressor gene
was finally revealed in 1989 by Bert Vogelstein
working at Johns Hopkins School of Medicine
.
Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation. In a series of publications in 1991-92, Michael Kastan, Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.
In 1992, Wafik El-Deiry
when he was working with Bert Vogelstein
at Johns Hopkins University identified the consensus sequence
, to which human p53 could bind, by immunoprecipitating human genomic DNA that could be bound by baculovirus
-produced human p53 protein. This sequence was published in the first issue of the journal Nature Genetics in 1992 in work that is highly cited. The consensus sequence is 5'-RRRCWWGYYY-N(0-13)-RRRCWWGYYY-3' and is located in the regulatory regions of genes that are activated by the p53 transcription factor. The presence of p53 response elements in or around genes (promoters, upstream sequences, introns) is a powerful predictor of regulation and activation of a particular gene by p53.
In 1993, p53 was voted molecule of the year by Science
magazine.
That same year, 1993, Wafik El-Deiry when he was working with Bert Vogelstein at Johns Hopkins University discovered p21(WAF1) as a gene regulated directly by p53. This work was reported in the most highly cited paper ever published in the journal Cell, and provided a molecular mechanism by which mammalian cells undergo growth arrest when damaged. The p21(WAF1) protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21(WAF1) protein.
with
Multicellular organism
Multicellular organisms are organisms that consist of more than one cell, in contrast to single-celled organisms. Most life that can be seen with the the naked eye is multicellular, as are all animals and land plants.-Evolutionary history:Multicellularity has evolved independently dozens of times...
s, where it regulates the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
and, thus, functions as a tumor suppressor that is involved in preventing cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. As such, p53 has been described as "the guardian of the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
", the "guardian angel gene", and the "master watchman", referring to its role in conserving stability by preventing genome mutation.
The name p53 is in reference to its apparent molecular mass
Molecular mass
The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...
: It runs as a 53-kilodalton (kDa) protein on SDS-PAGE
SDS-PAGE
SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis, describes a collection of related techniques widely used in biochemistry, forensics, genetics and molecular biology to separate proteins according to their electrophoretic mobility...
. But, based on calculations from its amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues, p53's mass is actually only 43.7 kDa. This difference is due to the high number of proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
residues in the protein, which slow its migration on SDS-PAGE
SDS-PAGE
SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis, describes a collection of related techniques widely used in biochemistry, forensics, genetics and molecular biology to separate proteins according to their electrophoretic mobility...
, thus making it appear heavier than it actually is. This effect is observed with p53 from a variety of species, including humans, rodents, frogs, and fish.
Nomenclature
p53 is also known as:- UniProt name: Cellular tumor antigenTumor antigenTumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.- Mechanism of tumor antigenesis:...
p53 - Antigen NY-CO-13
- Phosphoprotein p53
- Transformation-related protein 53 (TRP53)
- Tumor suppressor p53
Gene
In humans, p53 is encoded by the TP53 gene located on the short arm of chromosome 17Chromosome 17 (human)
125px|rightChromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 81 million base pairs and represents between 2.5 and 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of...
(17p13.1). The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb.The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53. TP53 orthologs have been identified in most mammals for which complete genome data are available.
In humans, a common polymorphism
Polymorphism
Polymorphism or dimorphism may refer to:-Biology:* Polymorphism , including:** having multiple phenotypes within a population; the switch that determines which phenotype an individual displays can be genetic or environmental...
involves the substitution of an arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
for a proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility, however, a combined analysis did not show a link.
For these mammals, the gene is located on different chromosomes:
- Chimp and orangutanOrangutanOrangutans are the only exclusively Asian genus of extant great ape. The largest living arboreal animals, they have proportionally longer arms than the other, more terrestrial, great apes. They are among the most intelligent primates and use a variety of sophisticated tools, also making sleeping...
, chromosome 17 - MacaqueMacaqueThe macaques constitute a genus of Old World monkeys of the subfamily Cercopithecinae. - Description :Aside from humans , the macaques are the most widespread primate genus, ranging from Japan to Afghanistan and, in the case of the barbary macaque, to North Africa...
, chromosome 16 - Mouse, chromosome 11
- Rat, chromosome 10
- DogDogThe domestic dog is a domesticated form of the gray wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...
, chromosome 5 - Cow, chromosome 19
- PigPigA pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...
, chromosome 12 - HorseHorseThe horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...
, chromosome 11 - Opossum, chromosome 2
(Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.)
Structure
Human p53 is 393 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s long and has seven domains:
- an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factorTranscription factorIn molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s: residues 1-42. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes. - activation domain 2 (AD2) important for apoptoticApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
activity: residues 43-63. - ProlineProlineProline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
rich domain important for the apoptotic activity of p53: residues 64-92. - central DNADNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
-binding core domain (DBDDNA-binding domainA DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
). Contains one zinc atom and several arginineArginineArginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
amino acids: residues 102-292. This region is responsible for binding the p53 co-repressor LMO3LMO3LIM domain only protein 3 is a transcription co-factor, which in humans is encoded by the LMO3 gene. LMO3 interacts with the tumor suppressor p53 and regulates its function. LMO3 is considered to be an oncogene in Neuroblastoma.-Further reading:...
. - nuclear localization signaling domain, residues 316-325.
- homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 in vivo.
- C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393.
A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53.
KO mutations
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
and position for p53 interaction with TFIID are listed below:
9aaTADs mediate p53 interaction with general coactivators - TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA).
Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore OD mutations have a dominant negative effect on the function of p53.
Wild-type p53 is a labile protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, comprising folded and unstructured regions
Intrinsically unstructured proteins
Intrinsically unstructured proteins, often referred to as naturally unfolded proteins or disordered proteins, are proteins characterized by lack of stable tertiary structure when the protein exists as an isolated polypeptide chain under physiological conditions in vitro...
that function in a synergistic manner.
Function
p53 has many mechanisms of anticancer function, and plays a role in apoptosis, genomic stability, and inhibition of angiogenesisAngiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. In its anti-cancer role, p53 works through several mechanisms:
- It can activate DNA repairDNA repairDNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
proteins when DNA has sustained damage. - It can induce growth arrest by holding the cell cycleCell cycleThe cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle). - It can initiate apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, the programmed cell death, if DNA damage proves to be irreparable.
Activated p53 binds DNA and activates expression of several genes including WAF1/CIP1 encoding for p21
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
. p21 (WAF1) binds to the G1
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
-S
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
/CDK
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(CDK2) and S/CDK complexes (molecules important for the G1/S transition
G1/S transition
The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase and the S phase.It is a "point of no return" beyond which the cell is committed to dividing; in yeast this is called START and in multicellular eukaryotes it is termed the restriction point....
in the cell cycle) inhibiting their activity.
When p21(WAF1) is complexed with CDK2 the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Thus, cells will divide uncontrollably, and form tumors.
Recent research has also linked the p53 and RB1
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
pathways, via p14ARF, raising the possibility that the pathways may regulate each other.
p53 by regulating LIF
Leukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...
has been shown to facilitate implantation in the mouse model and possibly in humans.
p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning
Sun tanning
Sun tanning or simply tanning is the process whereby skin color is darkened or tanned. The process is most often a result of exposure to ultraviolet radiation from the sun or from artificial sources, such as a tanning bed, but can also be a result of windburn or reflected light...
.
Regulation
p53 becomes activated in response to a myriad of stress types, which include but are not limited to DNA damage (induced by either UVUltraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
, IR
Ionizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
, or chemical agents such as hydrogen peroxide), oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, osmotic shock
Osmotic shock
Osmotic shock or osmotic stress is a sudden change in the solute concentration around a cell, causing a rapid change in the movement of water across its cell membrane. Under conditions of high concentrations of either salts, substrates or any solute in the supernatant, water is drawn out of the...
, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
forces p53 to be activated as a transcription regulator
Transcriptional regulation
Transcriptional regulation is the change in gene expression levels by altering transcription rates. -Regulation of transcription:Regulation of transcription controls when transcription occurs and how much RNA is created...
in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.
The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM
Ataxia telangiectasia mutated
Ataxia telangiectasia mutated is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis...
, CHK1 and CHK2, DNA-PK, CAK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF
P14arf
p14ARF is an alternate reading frame product of the CDKN2A locus. Both p16INK4a and p14ARF are involved in cell cycle regulation. p14ARF inhibits mdm2, thus promoting p53, which promotes p21 activation, which then binds and inactivates certain cyclin-CDK complexes, which would otherwise promote...
.
In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
(also called HDM2 in humans), which is itself a product of p53, binds to p53, preventing its action and transports it from the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
to the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. Also Mdm2 acts as ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
and covalently attaches ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
to p53 and thus marks p53 for degradation by the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
. However, ubiquitylation of p53 is reversible. A ubiquitin specific protease, USP7
USP7
Ubiquitin-specific-processing protease 7 also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease is an enzyme that in humans is encoded by the USP7 gene....
(or HAUSP
USP7
Ubiquitin-specific-processing protease 7 also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease is an enzyme that in humans is encoded by the USP7 gene....
), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation. This is one means by which p53 is stabilized in response to oncogenic insults.
Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300
EP300
E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...
or PCAF
PCAF
P300/CBP-associated factor , also known as K acetyltransferase 2B , is a human gene and trancriptional coactivator associated with p53.-Structure:...
, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7
SIRT7
NAD-dependent deacetylase sirtuin-7 is an enzyme that in humans is encoded by the SIRT7 gene.-Further reading:...
, can deacetylate p53, leading to an inhibition of apoptosis. Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.
Role in disease
Li-Fraumeni syndrome
Li-Fraumeni syndrome is an extremely rare autosomal dominant hereditary disorder. It is named after Frederick Pei Li and Joseph F. Fraumeni, Jr., the American physicians who first recognized and described the syndrome. Li-Fraumeni syndrome greatly increases susceptibility to cancer...
. The TP53 gene can also be damaged in cells by mutagen
Mutagen
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...
s (chemicals
Chemical substance
In chemistry, a chemical substance is a form of matter that has constant chemical composition and characteristic properties. It cannot be separated into components by physical separation methods, i.e. without breaking chemical bonds. They can be solids, liquids or gases.Chemical substances are...
, radiation
Radiation
In physics, radiation is a process in which energetic particles or energetic waves travel through a medium or space. There are two distinct types of radiation; ionizing and non-ionizing...
, or virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es), increasing the likelihood that the cell will begin decontrolled division. More than 50 percent of human
Human
Humans are the only living species in the Homo genus...
tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s contain a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
or deletion
Genetic deletion
In genetics, a deletion is a mutation in which a part of a chromosome or a sequence of DNA is missing. Deletion is the loss of genetic material. Any number of nucleotides can be deleted, from a single base to an entire piece of chromosome...
of the TP53 gene. Increasing the amount of p53, which may initially seem a good way to treat tumors or prevent them from spreading, is in actuality not a usable method of treatment, since it can cause premature aging. However, restoring endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
p53 function holds a lot of promise. Loss of p53 creates genomic instability that most often results in the aneuploidy
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
phenotype.
Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
(HPV), encodes a protein, E6, which binds the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, pRb
PRB
PRB may refer to:* PRB , the Australian Automotive Manufacturer* PRB * The unofficial ISO 4217 code for the Transnistrian rublePRB is short for:* Powder River Basin, a major coal producing geologic basin in the USA...
, by the HPV protein E7, allows for repeated cell division manifested in the clinical disease of wart
Wart
A wart is generally a small, rough growth, typically on a human’s hands or feet but often other locations, that can resemble a cauliflower or a solid blister. They are caused by a viral infection, specifically by human papillomavirus 2 and 7. There are as many as 10 varieties of warts, the most...
s. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
over the years can cause irreversible changes leading to carcinoma in situ
Carcinoma in situ
Carcinoma in situ is an early form of cancer that is defined by the absence of invasion of tumor cells into the surrounding tissue, usually before penetration through the basement membrane. In other words, the neoplastic cells proliferate in their normal habitat, hence the name "in situ"...
and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.
In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop, MDM2 is itself induced by the p53 protein. However, mutant p53 proteins often do not induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels.
Discovery
p53 was identified in 1979 by Lionel CrawfordLionel Crawford
Lionel Vivian Crawford FRS FRSE is a British cancer expert and virologist.He was educated at Rendcomb College between 1941 and 1950 before being called up for National Service. After demobilization in 1952 he studied at Emmanuel College, Cambridge with a State Scholarship, graduating with a first...
, David P. Lane
David P. Lane
Sir David Philip Lane FRS, FRSE FRCPath is a British oncologist. He is best known for his work on the p53 tumour suppressor protein. Besides his position at the University of Dundee, he also founded the Cyclacel biotechnology company and is the Chief Scientist of Cancer Research UK.He was made a...
, Arnold Levine, and Lloyd Old
Lloyd Old
Dr. Lloyd J. Old is internationally recognized as one of the founders and standard-bearers of the field of cancer immunology. When Dr. Old began his career in 1958, tumor immunology was in its infancy. Today, cancer immunotherapies are emerging as a significant advance in cancer therapy...
, working at Imperial Cancer Research Fund (UK) Princeton University
Princeton University
Princeton University is a private research university located in Princeton, New Jersey, United States. The school is one of the eight universities of the Ivy League, and is one of the nine Colonial Colleges founded before the American Revolution....
/UMDNJ (Cancer Institute of New Jersey), and Sloan-Kettering Memorial Hospital, respectively. It had been hypothesized to exist before as the target of the SV40
SV40
SV40 is an abbreviation for Simian vacuolating virus 40 or Simian virus 40, a polyomavirus that is found in both monkeys and humans...
virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences
Russian Academy of Sciences
The Russian Academy of Sciences consists of the national academy of Russia and a network of scientific research institutes from across the Russian Federation as well as auxiliary scientific and social units like libraries, publishers and hospitals....
in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science
Weizmann Institute of Science
The Weizmann Institute of Science , known as Machon Weizmann, is a university and research institute in Rehovot, Israel. It differs from other Israeli universities in that it offers only graduate and post-graduate studies in the sciences....
). The human TP53 gene was cloned in 1984 and the full length clone in 1985.
It was initially presumed to be an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
due to the use of mutated cDNA following purification of tumour cell mRNA. Its character as a tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
was finally revealed in 1989 by Bert Vogelstein
Bert Vogelstein
Bert Vogelstein is a Howard Hughes Medical Institute investigator at The Johns Hopkins University. He clarified the role of the gene p53, which repairs DNA in dividing cells and destroys the cell if its DNA cannot be repaired. Damaged p53 is responsible for half of all cancers...
working at Johns Hopkins School of Medicine
Johns Hopkins School of Medicine
The Johns Hopkins School of Medicine , located in Baltimore, Maryland, U.S., is the academic medical teaching and research arm of Johns Hopkins University. Hopkins has consistently been the nation's number one medical school in the amount of competitive research grants awarded by the National...
.
Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation. In a series of publications in 1991-92, Michael Kastan, Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.
In 1992, Wafik El-Deiry
Wafik El-Deiry
Wafik El-Deiry is an associate Professor of Medicine and Genetics at the University of Pennsylvania School of Medicine. He is also a member of the University of Pennsylvania Comprehensive Cancer Center and Institute for Human Gene Therapy...
when he was working with Bert Vogelstein
Bert Vogelstein
Bert Vogelstein is a Howard Hughes Medical Institute investigator at The Johns Hopkins University. He clarified the role of the gene p53, which repairs DNA in dividing cells and destroys the cell if its DNA cannot be repaired. Damaged p53 is responsible for half of all cancers...
at Johns Hopkins University identified the consensus sequence
Consensus sequence
In molecular biology and bioinformatics, consensus sequence refers to the most common nucleotide or amino acid at a particular position after multiple sequences are aligned. A consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are...
, to which human p53 could bind, by immunoprecipitating human genomic DNA that could be bound by baculovirus
Baculovirus
The baculoviruses are a family of large rod-shaped viruses that can be divided to two genera: nucleopolyhedroviruses and granuloviruses . While GVs contain only one nucleocapsid per envelope, NPVs contain either single or multiple nucleocapsids per envelope. The enveloped virions are further...
-produced human p53 protein. This sequence was published in the first issue of the journal Nature Genetics in 1992 in work that is highly cited. The consensus sequence is 5'-RRRCWWGYYY-N(0-13)-RRRCWWGYYY-3' and is located in the regulatory regions of genes that are activated by the p53 transcription factor. The presence of p53 response elements in or around genes (promoters, upstream sequences, introns) is a powerful predictor of regulation and activation of a particular gene by p53.
In 1993, p53 was voted molecule of the year by Science
Science (journal)
Science is the academic journal of the American Association for the Advancement of Science and is one of the world's top scientific journals....
magazine.
That same year, 1993, Wafik El-Deiry when he was working with Bert Vogelstein at Johns Hopkins University discovered p21(WAF1) as a gene regulated directly by p53. This work was reported in the most highly cited paper ever published in the journal Cell, and provided a molecular mechanism by which mammalian cells undergo growth arrest when damaged. The p21(WAF1) protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21(WAF1) protein.
Interactions
p53 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with
- ANKRD2ANKRD2Ankyrin repeat domain-containing protein 2 is a protein that in humans is encoded by the ANKRD2 gene.-Interactions:ANKRD2 has been shown to interact with Y box binding protein 1, Telethonin, Promyelocytic leukemia protein and P53.-Further reading:...
- AprataxinAprataxinAprataxin is a protein that in humans is encoded by the APTX gene.-Interactions:Aprataxin has been shown to interact with XRCC1, PARP1 and P53.-External links:**...
- Ataxia telangiectasia and Rad3 relatedAtaxia telangiectasia and Rad3 relatedSerine/threonine-protein kinase ATR also known as ataxia telangiectasia and Rad3-related protein or FRAP-related protein 1 is an enzyme that in humans is encoded by the ATR gene...
- Ataxia telangiectasia mutatedAtaxia telangiectasia mutatedAtaxia telangiectasia mutated is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis...
- ATF3ATF3Cyclic AMP-dependent transcription factor ATF-3 is a protein that, in humans, is encoded by the ATF3 gene.-Interactions:ATF3 has been shown to interact with JunD, C-jun, Mothers against decapentaplegic homolog 3, DNA damage-inducible transcript 3 and P53.- External links :...
, - Aurora A kinaseAurora A kinaseAurora A kinase also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.Aurora A is a member of a family of mitotic serine/threonine kinases. It is implicated with important processes during mitosis and meiosis whose proper function is integral for...
- BAK1
- BARD1BARD1BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the BARD1 gene.-Interactions:BARD1 has been shown to interact with BRE, UBE2D1, CSTF2, BRCC3, RAD51, BCL3, TACC1, Ewing sarcoma breakpoint region 1, FANCD2, H2AFX, CSTF1, NPM1, BRCA2, BRCA1, P53 and Aurora B...
- Bloom syndrome proteinBloom syndrome proteinBloom syndrome protein is a protein that in humans is encoded by the BLM gene and is expressed in Bloom syndrome.The Bloom syndrome gene product is related to the RecQ subset of DExH box-containing DNA helicases and has both DNA-stimulated ATPase and ATP-dependent DNA helicase activities...
- BRCA1BRCA1BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
- BRCA2BRCA2BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
- BRCC3BRCC3Lys-63-specific deubiquitinase BRCC36 is an enzyme that in humans is encoded by the BRCC3 gene.-Interactions:BRCC3 has been shown to interact with BRE, BRCA2, RAD51, BRCA1, P53 and BARD1.-Further reading:...
- BREBRE (gene)BRCA1-A complex subunit BRE is a protein that in humans is encoded by the BRE gene.-Interactions:BRE has been shown to interact with BRCA2, RAD51, BRCC3, BRCA1, C19orf62, P53 and BARD1.-Further reading:...
- CCAAT/enhancer binding protein zetaCCAAT/enhancer binding protein zetaCCAAT/enhancer-binding protein zeta is a protein that in humans is encoded by the CEBPZ gene.-Interactions:CCAAT/enhancer binding protein zeta has been shown to interact with NFYB, P73 and P53....
- CDC14ACDC14ADual specificity protein phosphatase CDC14A is an enzyme that in humans is encoded by the CDC14A gene.-Further reading:...
- Cdk1Cdk1Cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S....
- CFLARCFLARCASP8 and FADD-like apoptosis regulator is a protein that in humans is encoded by the CFLAR gene. Also called FLICE-like inhibitory protein .-Further reading:...
- CHEK1CHEK1Serine/threonine-protein kinase Chk1 is an enzyme that in humans is encoded by the CHEK1 gene.Chk1 is a kinase that phosphorylates cdc25, an important phosphatase in cell cycle control, particularly for entry into mitosis. Cdc25, when phosphorylated on serine 216 by chk1 becomes bound by an adaptor...
- CREB-binding protein
- CREB1CREB1CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the CREB1 gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters...
- Cyclin HCyclin HCyclin-H is a protein that in humans is encoded by the CCNH gene.-Interactions:Cyclin H has been shown to interact with P53, Cyclin-dependent kinase 7 and MNAT1.-Further reading:...
- Cyclin-dependent kinase 7Cyclin-dependent kinase 7Cell division protein kinase 7 is an enzyme that in humans is encoded by the CDK7 gene.The protein encoded by this gene is a member of the cyclin-dependent protein kinase family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces...
- DNA-PKcs
- E4F1E4F1Transcription factor E4F1 is a protein that in humans is encoded by the E4F1 gene.-Interactions:E4F1 has been shown to interact with P16, Retinoblastoma protein and P53....
- EFEMP2EFEMP2EGF-containing fibulin-like extracellular matrix protein 2 is a protein that in humans is encoded by the EFEMP2 gene.-External links:*...
- EP300EP300E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...
- ERCC6ERCC6DNA excision repair protein ERCC-6 is a protein that in humans is encoded by the ERCC6 gene.-External links:*...
- GNL3GNL3Guanine nucleotide-binding protein-like 3 also known as nucleostemin is a protein that in humans is encoded by the GNL3 gene. It is found within the nucleolus that binds p53. Nucleostemin regulates the cell cycle and affects cell differentiation, decreasing in amount as this differentiation...
- GPS2GPS2 (gene)G protein pathway suppressor 2 is a protein that in humans is encoded by the GPS2 gene.-Interactions:GPS2 has been shown to interact with Cyclin A1, TBL1X, Nuclear receptor co-repressor 1, P53, EP300, HDAC3 and C21orf7.-Further reading:...
- GSK3BGSK3BGlycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
- Heat shock protein 90kDa alpha (cytosolic), member A1
- HIF1AHIF1AHypoxia-inducible factor 1, alpha subunit , also known as HIF1A, is a protein that in humans is encoded by the HIF1A gene...
- HIPK1HIPK1Homeodomain-interacting protein kinase 1 is an enzyme that in humans is encoded by the HIPK1 gene.-Further reading:...
- HIPK2HIPK2Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene.-Interactions:HIPK2 has been shown to interact with SKI protein, Death associated protein 6, P53, CREB binding protein, Mothers against decapentaplegic homolog 1, TP53INP1 and RANBP9.-Further reading:...
- HMGB1HMGB1High-mobility group protein B1, also known as high-mobility group protein 1 and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.HMG-1 belongs to high mobility group.-Role in Inflammation:...
- HSPA9HSPA9Stress-70 protein, mitochondrial is a protein that in humans is encoded by the HSPA9 gene.-Interactions:HSPA9 has been shown to interact with FGF1 and P53.- External links :...
- HuntingtinHuntingtinThe Huntingtin gene, also called HTT or HD gene, is the IT15 gene which codes for a protein called the huntingtin protein...
- ING1ING1Inhibitor of growth protein 1 is a protein that in humans is encoded by the ING1 gene.-Location on Chromosome 13:ING1 is located near the following genes on Chromosome 13*CARKD Carbohydrate Kinase Domain-Containing Protein...
- ING4ING4Inhibitor of growth protein 4 is a protein that in humans is encoded by the ING4 gene.-Interactions:ING4 has been shown to interact with EP300, RELA and P53.-Further reading:...
- ING5ING5Inhibitor of growth protein 5 is a protein that in humans is encoded by the ING5 gene.-Interactions:ING5 has been shown to interact with EP300 and P53.-Further reading:...
ELLELL (gene)RNA polymerase II elongation factor ELL is an enzyme that in humans is encoded by the ELL gene.-Further reading:...
, - IκBα
- KPNB1KPNB1Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.-Interactions:KPNB1 has been shown to interact with NUP98, Karyopherin alpha 1, KPNA3, Karyopherin alpha 2, SMN1, Parathyroid hormone-related protein, Nucleoporin 62, RANBP2, Ran , RANBP1, NUP50, P53, NUP153 and...
- Mdm2Mdm2Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
- MDM4MDM4Protein Mdm4 is a protein that in humans is encoded by the MDM4 gene.-Interactions:MDM4 has been shown to interact with E2F1, Mdm2 and P53.-Further reading:...
- MED1MED1Mediator of RNA polymerase II transcription subunit 1 is a protein that in humans is encoded by the MED1 gene.- Function :The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with...
- Mitogen-activated protein kinase 9Mitogen-activated protein kinase 9Mitogen-activated protein kinase 9 is an enzyme that in humans is encoded by the MAPK9 gene.-Interactions:Mitogen-activated protein kinase 9 has been shown to interact with TOB1, Grb2, MAPK8IP2, P53, MAPK8IP3 and MAPK8IP1.-Further reading:...
- MNAT1MNAT1CDK-activating kinase assembly factor MAT1 is an enzyme that in humans is encoded by the MNAT1 gene.-Interactions:MNAT1 has been shown to interact with POU2F1, MTA1, Cyclin H, P53, Estrogen receptor alpha, MCM7 and Cyclin-dependent kinase 7....
- Multisynthetase complex auxiliary component p38Multisynthetase complex auxiliary component p38Aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 is an enzyme that in humans is encoded by the AIMP2 gene.-Interactions:...
- NDNNDN (gene)Necdin is a protein that in humans is encoded by the NDN gene.-Interactions:NDN has been shown to interact with NUCB2, E2F1, IL1A, Low affinity nerve growth factor receptor, P53 and HNRNPU.-Further reading:...
- NucleolinNucleolinNucleolin is a protein that in humans is encoded by the NCL gene.- Gene :The human NCL gene is located on chromosome 2 and consists of 14 exons with 13 introns and spans approximately 11kb...
- NUMBNUMB (gene)Protein numb homolog is a protein that in humans is encoded by the NUMB gene.-Interactions:NUMB has been shown to interact with Adaptor-related protein complex 2, alpha 1, Mdm2, L1, DPYSL2, SIAH1, P53 and LNX1.-Further reading:...
- P16P16 (gene)Cyclin-dependent kinase inhibitor 2A, also known as multiple tumor suppressor 1 , is a tumor suppressor protein, that in humans is encoded by the CDKN2A gene...
- PARCPARC (gene)Cullin-9 is a protein that in humans is encoded by the CUL9 gene.-Interactions:PARC has been shown to interact with P53.-Further reading:...
- PARP1PARP1Poly [ADP-ribose] polymerase 1 also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene.- Function :PARP1 works:...
- PIAS1PIAS1E3 SUMO-protein ligase PIAS1 is an enzyme that in humans is encoded by the PIAS1 gene.-Interactions:PIAS1 has been shown to interact with DNMT3A, STAT1, Small ubiquitin-related modifier 1, Sp3 transcription factor, UBE2I and P53.-Further reading:...
CDC14BCDC14BDual specificity protein phosphatase CDC14B is an enzyme that in humans is encoded by the CDC14B gene.-Interactions:CDC14B has been shown to interact with p53.. However, this interaction has not been reported in other studies.-Further reading:... - PIN1PIN1Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene.-Interactions:PIN1 has been shown to interact with CSNK2A2, Casein kinase 2, alpha 1, Wee1-like protein kinase, FOXO4, CDC25C, CDC27, MYT1, PLK1, MPHOSPH1, DAB2, P53, PKMYT1, C-jun,...
- PLAGL1PLAGL1Zinc finger protein PLAGL1 is a protein that in humans is encoded by the PLAGL1 gene.-Further reading:...
- PLK3PLK3Polo-like kinase 3 , also known as PLK3, is an enzyme which in humans is encoded by the PLK3 gene.- Function :Cytokine-inducible kinase is a putative serine/threonine kinase. CNK contains both a catalytic domain and a putative regulatory domain...
- PRKRAPRKRAProtein kinase, interferon-inducible double stranded RNA dependent activator, also known as interferon-inducible double stranded RNA-dependent protein kinase activator A or Protein ACTivator of the interferon-induced protein kinase is a protein that in humans is encoded by the PRKRA gene...
- ProhibitinProhibitinProhibitin, also known as PHB, is a protein that in humans is encoded by the PHB gene.The Phb gene has also been described in animals, fungi, plants, and unicellular eukaryotes. Prohibitins are divided in two classes, termed Type-I and Type-II prohibitins, based on their similarity to yeast PHB1...
- Promyelocytic leukemia proteinPromyelocytic leukemia proteinProbable transcription factor PML is a tumor suppressor protein that in humans is encoded by the PML gene.-Interactions:Promyelocytic leukemia protein has been shown to interact with Retinoic acid receptor alpha, HDAC1, Nerve Growth factor IB, SKI protein, Zinc finger and BTB domain-containing...
- Protein kinase RProtein kinase RProtein kinase RNA-activated also known as protein kinase R , interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 is an enzyme that in humans is encoded by the EIF2AK2 gene.PKR protects against viral...
- PSME3PSME3Proteasome activator complex subunit 3 is a protein that in humans is encoded by the PSME3 gene.-Interactions:PSME3 has been shown to interact with P53 and Mdm2.-Further reading:...
- PTENPTEN (gene)Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
- PTK2PTK2PTK2 protein tyrosine kinase 2 , also known as Focal Adhesion Kinase , is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes...
- PTTG1PTTG1Securin is a protein that in humans is encoded by the PTTG1 gene.-Interactions:PTTG1 has been shown to interact with RPS10, PTTG1IP, DNAJA1, Ku70 and P53.-Further reading:...
- RAD51RAD51RAD51 is a human gene. The protein encoded by this gene is a member of the RAD51 protein family which assist in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA and yeast Rad51...
- RCHY1RCHY1RING finger and CHY zinc finger domain-containing protein 1 is a protein that in humans is encoded by the RCHY1 gene.-Interactions:RCHY1 has been shown to interact with P53 and Androgen receptor.-Further reading:...
- Replication protein A1
- RPL11RPL1160S ribosomal protein L11 is a protein that in humans is encoded by the RPL11 gene.-Interactions:RPL11 has been shown to interact with P16, BLMH, Mdm2, Promyelocytic leukemia protein and P53.-External links:*...
- S100BS100BS100 calcium binding protein B or S100B is a protein of the S-100 protein family.S100 proteins are localized in the cytoplasm and nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation...
, - Small ubiquitin-related modifier 1Small ubiquitin-related modifier 1Small ubiquitin-related modifier 1 is a protein that in humans is encoded by the SUMO1 gene.Most cleft genes have a sumoylation component .-Interactions:...
- SMARCA4SMARCA4Transcription activator BRG1 also known as ATP-dependent helicase SMARCA4 is a protein that in humans is encoded by the SMARCA4 gene.- Function :...
, - SMARCB1SMARCB1SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the SMARCB1 gene.-Interactions:...
- SMN1SMN1Survival motor neuron protein is a protein that in humans is encoded by the SMN1 gene.-Interactions:SMN1 has been shown to interact with Gem-associated protein 7, GEMIN4, KPNB1, Survival of motor neuron protein-interacting protein 1, DDX20, Coilin, Small nuclear ribonucleoprotein D1, Fibrillarin,...
- TATA binding proteinTATA Binding ProteinThe TATA-binding protein is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 35 base pairs upstream of the transcription start site in some eukaryotic gene promoters...
- TFAP2ATFAP2ATranscription factor AP-2 alpha , also known as TFAP2A, is a protein that in humans is encoded by the TFAP2A gene.- Function :...
- TFDP1TFDP1Transcription factor Dp-1 is a protein that in humans is encoded by the TFDP1 gene.-Interactions:TFDP1 has been shown to interact with E2F1, E2F5 and P53.-Further reading:...
- TOP1TOP1DNA topoisomerase 1 is an enzyme that in humans is encoded by the TOP1 gene.-Interactions:TOP1 has been shown to interact with BTBD1, P53, Nucleolin, BTBD2, ASF/SF2 and UBE2I.-Further reading:...
- TOP2ATOP2ADNA topoisomerase 2-alpha is an enzyme that in humans is encoded by the TOP2A gene.-Interactions:TOP2A has been shown to interact with HDAC1, CDC5L, Small ubiquitin-related modifier 1 and P53.-Further reading:...
- TP53BP1TP53BP1Tumor suppressor p53-binding protein 1 also known as p53-binding protein 1 or 53BP1 is a protein that in humans is encoded by the TP53BP1 gene.- Clinical significance :53BP1 is underexpressed in most cases of triple-negative breast cancer....
- TP53BP2TP53BP2Apoptosis-stimulating of p53 protein 2 also known as Bcl2-binding protein and tumor suppressor p53-binding protein 2 is a protein that in humans is encoded by the TP53BP2 gene...
, TOP2BTOP2BDNA topoisomerase 2-beta is an enzyme that in humans is encoded by the TOP2B gene.-Interactions:TOP2B has been shown to interact with BAZ1B, HDAC1, Histone deacetylase 2, T-cell surface glycoprotein CD3 epsilon chain, Small ubiquitin-related modifier 1 and P53.-Further reading:...
, - TP53INP1TP53INP1Tumor protein p53-inducible nuclear protein 1 is a protein that in humans is encoded by the TP53INP1 gene. In mice this protein is also called TRP53INP1 and is encoded by the Trp53inp1 gene. The protein is also referred to as SIP or "stress inducible protein"-Interactions:TP53INP1 has been shown to...
- TSG101TSG101Tumor susceptibility gene 101, also known as TSG101, is a human gene that encodes for a cellular protein of the same name.-HIV:TSG101 seems to play an important role in the pathogenesis of HIV...
- UBE2AUBE2AUbiquitin-conjugating enzyme E2 A is a protein that in humans is encoded by the UBE2A gene.-Interactions:UBE2A has been shown to interact with RAD18 and P53.-Further reading:...
- UBE2IUBE2ISUMO-conjugating enzyme UBC9 is a protein that in humans is encoded by the UBE2I gene.-Interactions:UBE2I has been shown to interact with WT1, TOP1, RAD51, Activating transcription factor 2, PIAS1, SALL1, FHIT, RANBP2, Protein inhibitor of activated STAT2, DNMT3A, DNMT3B, Small ubiquitin-related...
- Ubiquitin CUbiquitin CUbiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
- USP7USP7Ubiquitin-specific-processing protease 7 also known as ubiquitin carboxyl-terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease is an enzyme that in humans is encoded by the USP7 gene....
- Werner syndrome ATP-dependent helicase
- WWOXWWOXWW domain-containing oxidoreductase is an enzyme that in humans is encoded by the WWOX gene.- Function :WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA...
- XPBXPBXPB is an ATP dependent human DNA helicase that is a part of the TFIIH transcription factor complex.-Structure:The 3D structure of the archeael homologue of XPB has been solved by X-ray crystallography by Dr...
- Y box binding protein 1Y box binding protein 1Y box binding protein 1, officially known as YBX1, but commonly referred to as "YB-1" by researchers, is a human protein. Current research is examining its involvement in cancer, and particularly in the metastasis of cancerous cells or prevention thereof....
- YPEL3YPEL3Human YPEL3 is a recently discovered protein encoded by the YPEL3 gene, shown to have growth inhibitory effects in normal and tumor cell lines. One of five family members , YPEL3 was named in reference to its Drosophila melanogaster orthologue...
- YWHAZYWHAZ14-3-3 protein zeta/delta is a protein that in humans is encoded by the YWHAZ gene.-Interactions:YWHAZ has been shown to interact with TSC2, LIMK1, CDC25B, AKT1, BCAR1, Interleukin-9 receptor, C-Raf, HMGN1, Vimentin, Tau protein, Protein kinase Mζ, GP1BB, GP1BA, TNFAIP3, Bcl-2-associated death...
- Zif268Zif268EGR-1 also known as Zif268 or NGFI-A is a protein that in humans is encoded by the EGR1 gene....
- ZNF148ZNF148Zinc finger protein 148 is a protein that in humans is encoded by the ZNF148 gene.-Interactions:ZNF148 has been shown to interact with PTRF and P53.- External links :...
External links
- a humorous song describing p53 structure and function
- GeneReviews/NCBI/NIH/UW entry on Li-Fraumeni Syndrome
- TUMOR PROTEIN p53 @ OMIM
- p53 @ The Atlas of Genetics and Cytogenetics in Oncology and Haematology
- TP53 Gene @ GeneCards
- p53 News provided by insciences organisation
- IARC TP53 Somatic Mutations database maintained at IARC, Lyon, by Magali Olivier