P16 (gene)
Encyclopedia
Cyclin-dependent kinase inhibitor 2A, (CDKN2A, p16Ink4A) also known as multiple tumor suppressor 1 (MTS-1), is a tumor suppressor
protein
, that in humans is encoded by the CDKN2A gene
. P16 plays an important role in regulating the cell cycle
, and mutations in p16 increase the risk of developing a variety of cancers, notably melanoma
.
generates several transcript
variants which differ in their first exon
s. At least three alternatively-spliced
variants encoding distinct proteins have been reported, two of which encode structurally related isoforms
known to function as inhibitors
of CDK4 kinase
. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF)
that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, MDM2
, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene.
Increased expression of the p16 gene as organisms age reduces the proliferation of stem cell
s. This reduction in the division and production of stem cells protects against cancer
while increasing the risks associated with cellular senescence
.
Pancreatic adenocarcinoma
is often associated with mutations in the CDKN2A gene.
Homozygous deletion of p16 are frequently found in esophageal cancer
and gastric cancer cell lines.
Concentrations of p16INK4a increase dramatically as tissue ages. Therefore p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.
with SERTAD1
, CCNG1
, Death associated protein 6
, P53
, E4F1
, Cyclin-dependent kinase 4
, Cyclin-dependent kinase 6
, Mdm2
, RPL11
and PPP1R9B
.
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...
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...
, that in humans is encoded by the CDKN2A gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. P16 plays an important role in regulating 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 mutations in p16 increase the risk of developing a variety of cancers, notably melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
.
Function
This geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
generates several transcript
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
variants which differ in their first exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s. At least three alternatively-spliced
Splicing (genetics)
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
variants encoding distinct proteins have been reported, two of which encode structurally related isoforms
Protein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
known to function as inhibitors
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of CDK4 kinase
Cyclin-dependent kinase 4
Cyclin-dependent kinase 4 is part of the cyclin-dependent kinase family.It is regulated by Cyclin D.-Interactions:Cyclin-dependent kinase 4 has been shown to interact with SERTAD1, CDC37, CEBPA, PCNA, Cyclin D3, Cyclin D1, CDKN2C, MyoD, P16, CDKN2B, Drebrin-like and CDKN1B.-External links:...
. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF)
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...
that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, 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...
, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene.
Increased expression of the p16 gene as organisms age reduces the proliferation of stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s. This reduction in the division and production of stem cells protects against 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...
while increasing the risks associated with cellular senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
.
Clinical significance
Mutations in the CDKN2A gene are associated with increased risk of a wide range of cancers and alterations of the gene are frequently seen in cancer cell lines. Examples include:Pancreatic adenocarcinoma
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
is often associated with mutations in the CDKN2A gene.
Homozygous deletion of p16 are frequently found in esophageal cancer
Esophageal cancer
Esophageal cancer is malignancy of the esophagus. There are various subtypes, primarily squamous cell cancer and adenocarcinoma . Squamous cell cancer arises from the cells that line the upper part of the esophagus...
and gastric cancer cell lines.
Concentrations of p16INK4a increase dramatically as tissue ages. Therefore p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.
Interactions
P16 (gene) 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 SERTAD1
SERTAD1
SERTA domain-containing protein 1 is a protein that in humans is encoded by the SERTAD1 gene.-Interactions:SERTAD1 has been shown to interact with P16, Cyclin-dependent kinase 4 and CREB-binding protein.-Further reading:...
, CCNG1
CCNG1
Cyclin-G1 is a protein that in humans is encoded by the CCNG1 gene.-Interactions:CCNG1 has been shown to interact with P16, Mdm2, PPP2R4 and P53.-Further reading:...
, Death associated protein 6
Death associated protein 6
Death-associated protein 6 also known as DAXX is a protein that in humans is encoded by the DAXX gene.- Function :DAXX, a death-domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death receptor Fas...
, P53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, E4F1
E4F1
Transcription 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....
, Cyclin-dependent kinase 4
Cyclin-dependent kinase 4
Cyclin-dependent kinase 4 is part of the cyclin-dependent kinase family.It is regulated by Cyclin D.-Interactions:Cyclin-dependent kinase 4 has been shown to interact with SERTAD1, CDC37, CEBPA, PCNA, Cyclin D3, Cyclin D1, CDKN2C, MyoD, P16, CDKN2B, Drebrin-like and CDKN1B.-External links:...
, Cyclin-dependent kinase 6
Cyclin-dependent kinase 6
Cell division protein kinase 6 is an enzyme that in humans is encoded by the CDK6 gene.It is regulated by Cyclin D.-Interactions:Cyclin-dependent kinase 6 has been shown to interact with CDKN2C, P16, PPM1B, Cyclin D3, Cyclin D1 and PPP2CA....
, 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...
, RPL11
RPL11
60S 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:*...
and PPP1R9B
PPP1R9B
Neurabin-2 is a protein that in humans is encoded by the PPP1R9B gene.-Interactions:PPP1R9B has been shown to interact with PPP1CB, PPP1CA, Dopamine receptor D2, P16, PPP1CC, T-cell lymphoma invasion and metastasis-inducing protein 1 and PPP1R2....
.