p21

This article is about the p21^Cip1 protein. For the p21/ras protein, see Ras (protein). For other uses, see P21 (disambiguation).

p21^Cip1 (alternatively p21^Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor that inhibits the complexes of CDK2 and CDK1. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.

Function

p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G₁ and S phase. In addition to growth arrest, p21 can mediate cellular senescence. One of the ways it was discovered was as a senescent cell-derived inhibitor.

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.

Studies of human embryonic stem cells (hESCs) commonly report the nonfunctional p53-p21 axis of the G1/S checkpoint pathway, and its relevance for cell cycle regulation and the DNA damage response (DDR). p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.

p21 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 caspases, 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.

Sometimes p21 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.

Despite regulation by tumor suppressor gene p53, 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.

Clinical significance

p21 mediates the resistance of hematopoietic cells to an infection with HIV 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.

Interactions

P21 has been shown to interact with:

• Nrf2
• BCCIP,
• CIZ1,
• CUL4A,
• CCNE1,
• CDK,
• DDB1,
• DTL,
• GADD45A,
• GADD45G,
• PCNA,
• PIM1,
• TK1, and
• TSG101.

External links

• Cyclin-Dependent Kinase Inhibitor p21 at the US National Library of Medicine Medical Subject Headings (MeSH)
• Drosophila dacapo - The Interactive Fly
• CDKN1A human gene location in the UCSC Genome Browser.
• CDKN1A human gene details in the UCSC Genome Browser.