P21
Encyclopedia
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 (6p21.2).
-CDK2
or -CDK4
complexes, and thus functions as a regulator of cell cycle
progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53
, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This was a major discovery in the early 1990s that revealed how cells stop dividing after being exposed to damaging agents such as radiation. In addition to growth arrest, p21 can mediate cellular senescence and one of the ways it was discovered was as a senescent cell-derived inhibitor. The p21(CIP1/WAF1) protein can also interact with proliferating cell nuclear antigen (PCNA
), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspase
s, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis
following caspase
activation. However p21 may inhibit apoptosis and does not induce cell death on its own. Two alternatively spliced variants, which encode an identical protein, have been reported.
{p21(CIP1/WAF1) is a CKI that directly inhibits the activity of cyclin E
/CDK2 and cyclin D
/CDK4/6 complexes. p21 functions as a regulator of cell cycle
progression at S phase
.} The expression of p21 is controlled by the tumor suppressor protein p53
. Sometimes,it is expressed without being induced by P53. This kind of induction plays a big role in p53 independent differentiation which is promoted by p21. Expression of p21 is mainly dependent on two factors 1) stimulus provided 2) type of the cell. Growth arrest by p21 can promote cellular differentiation. p21 therefore prevents cell proliferation.
The p21 protein also is important in the stress
response. p21 is a transcriptional target of the tumor suppressor gene, p53; despite this, loss-of-function mutations in p21 (unlike p53) do not accumulate in cancer nor do they predispose to cancer incidence. Mice genetically engineered to lack p21 develop normally and are not susceptible to cancer at a higher rate than wild-type mice (unlike p53 knockout mice).
Mice that lack the p21 gene gain the ability to regenerate
lost appendages.
by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus
. HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA. p21 expression affects at least two stages in the HIV life cycle inside CD4 T cells, significantly limiting production of new viruses.
Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.
with:
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 CDKN1A 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...
located on chromosome 6 (6p21.2).
Function
p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity of cyclinCyclin
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...
-CDK2
Cyclin-dependent kinase 2
Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...
or -CDK4
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:...
complexes, and thus functions as a regulator of 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...
progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein 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...
, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This was a major discovery in the early 1990s that revealed how cells stop dividing after being exposed to damaging agents such as radiation. In addition to growth arrest, p21 can mediate cellular senescence and one of the ways it was discovered was as a senescent cell-derived inhibitor. The p21(CIP1/WAF1) protein can also interact with proliferating cell nuclear antigen (PCNA
PCNA
Proliferating Cell Nuclear Antigen, commonly known as PCNA, is a protein that acts as a processivity factor for DNA polymerase δ in eukaryotic cells. It achieves this processivity by encircling the DNA, thus creating a topological link to the genome...
), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspase
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
s, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis
Apoptosis
Apoptosis 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...
following caspase
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
activation. However p21 may inhibit apoptosis and does not induce cell death on its own. Two alternatively spliced variants, which encode an identical protein, have been reported.
{p21(CIP1/WAF1) is a CKI that directly inhibits the activity of cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
/CDK2 and cyclin D
Cyclin D
Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition...
/CDK4/6 complexes. p21 functions as a regulator of 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...
progression at S phase
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...
.} The expression of p21 is controlled by the tumor suppressor protein 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...
. Sometimes,it is expressed without being induced by P53. This kind of induction plays a big role in p53 independent differentiation which is promoted by p21. Expression of p21 is mainly dependent on two factors 1) stimulus provided 2) type of the cell. Growth arrest by p21 can promote cellular differentiation. p21 therefore prevents cell proliferation.
The p21 protein also is important in the stress
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
response. p21 is a transcriptional target of the tumor suppressor gene, p53; despite this, loss-of-function mutations in p21 (unlike p53) do not accumulate in cancer nor do they predispose to cancer incidence. Mice genetically engineered to lack p21 develop normally and are not susceptible to cancer at a higher rate than wild-type mice (unlike p53 knockout mice).
Mice that lack the p21 gene gain the ability to regenerate
Regeneration (biology)
In biology, regeneration is the process of renewal, restoration, and growth that makes genomes, cells, organs, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of regeneration, from bacteria to humans. At its most...
lost appendages.
Clinical significance
p21 mediates the resistance of hematopoietic cells to an infection with HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus
Provirus
A provirus is a virus genome that is integrated into the DNA of a host cell.This state can be a stage of virus replication, or a state that persists over longer periods of time as either inactive viral infections or an endogenous retrovirus. In inactive viral infections the virus will not replicate...
. HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA. p21 expression affects at least two stages in the HIV life cycle inside CD4 T cells, significantly limiting production of new viruses.
Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.
Interactions
P21 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:
- Nrf2
- BCCIPBCCIPBRCA2 and CDKN1A-interacting protein is a protein that in humans is encoded by the BCCIP gene.-Interactions:BCCIP has been shown to interact with BRCA2, P21, and PTPmu -Further reading:...
- CIZ1CIZ1Cip1-interacting zinc finger protein is a protein that in humans is encoded by the CIZ1 gene.-Further reading:...
, - CUL4ACUL4ACullin-4A is a protein that in humans is encoded by the CUL4A gene.-Interactions:CUL4A has been shown to interact with Merlin, DDB2, CAND1, RBX1, DDB1 and P21.-Further reading:...
, - Cyclin E1Cyclin E1G1/S-specific cyclin-E1 is a protein that in humans is encoded by the CCNE1 gene.-Interactions:Cyclin E1 has been shown to interact with Retinoblastoma-like protein 2, Cdk1, CDC25A, Cyclin-dependent kinase 2, SMARCA4, CDKN1B, HERC5, CUL3 and P21....
, - Cyclin-dependent kinase 2Cyclin-dependent kinase 2Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...
, - DDB1DDB1DNA damage-binding protein 1 is a protein that in humans is encoded by the DDB1 gene.- Function :This gene encodes the large subunit of DNA damage-binding protein which is a heterodimer composed of a large and a small subunit. This protein functions in nucleotide excision repair...
, - DTLDTL (gene)Denticleless protein homolog is a protein that in humans is encoded by the DTL gene.-Further reading:...
, - GADD45AGADD45AGrowth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene.-Interactions:GADD45A has been shown to interact with, MAP3K4, Cdk1, Cyclin B1, PCNA, GADD45GIP1 and P21. Gadd45a has been recently shown that interacts with Aurora A...
, - GADD45GGADD45GGrowth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene.-Interactions:GADD45G has been shown to interact with MAP3K4, PCNA, GADD45GIP1 and P21.-Further reading:...
, - PCNAPCNAProliferating Cell Nuclear Antigen, commonly known as PCNA, is a protein that acts as a processivity factor for DNA polymerase δ in eukaryotic cells. It achieves this processivity by encircling the DNA, thus creating a topological link to the genome...
, - PIM1PIM1Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme that in humans is encoded by the PIM1 gene.Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murine T-cell lymphomas, as it was the locus...
, - Thymidine kinase 1Thymidine kinase 1Thymidine kinase 1, soluble , is a human thymidine kinase.Two forms of this protein have been identified in animal cells, one in cytosol and one in mitochondria...
, and - 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...
.