P21

p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a is_associated_with::cyclin-dependent kinase inhibitor that inhibits the complexes of is_associated_with::CDK2 and is_associated_with::CDK1. This protein is encoded by the CDKN1A is_associated_with::gene located on is_associated_with::chromosome 6 (6p21.2) in humans.

Function
p21 is a potent is_associated_with::cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity of is_associated_with::cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of is_associated_with::cell cycle progression at G1 and is_associated_with::S phase. In addition to growth arrest, p21 can mediate is_associated_with::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 is_associated_with::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 (is_associated_with::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 is_associated_with::CASP3-like is_associated_with::caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of is_associated_with::apoptosis following is_associated_with::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 is_associated_with::hematopoietic cells to an infection with is_associated_with::HIV by complexing with the HIV integrase and thereby aborting chromosomal integration of the is_associated_with::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:
 * is_associated_with::Nrf2
 * is_associated_with::BCCIP,
 * is_associated_with::CIZ1,
 * is_associated_with::CUL4A,
 * CCNE1,
 * CDK,
 * is_associated_with::DDB1,
 * DTL,
 * is_associated_with::GADD45A,
 * is_associated_with::GADD45G,
 * is_associated_with::PCNA,
 * is_associated_with::PIM1,
 * TK1, and
 * is_associated_with::TSG101.