Cyclin Dependent Kinase Inhibitor 1A (CDKN1A)

WAF1; p21; CIP1; p21WAF1; CAP20; CDKN1; MDA-6; SDI1; p21CIP1; CDK-Interacting Protein 1; Melanoma differentiation-associated protein 6

SPN	S147
HGNC	1784
MGI	104556
PubMed	22634755
RGD	69328
UniProt	P38936
Wiki	P21

The p21 (WAF1) protein binds to and inhibits the activity of cyclin-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.

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(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.

Reference

"The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases."
Cell 75:805-816(1993) [PubMed] [Europe PMC] [Abstract]

"WAF1, a potential mediator of p53 tumor suppression."
Cell 75:817-825(1993) [PubMed] [Europe PMC] [Abstract]

"p21 is a universal inhibitor of cyclin kinases."
Nature 366:701-704(1993) [PubMed] [Europe PMC] [Abstract]

"Use of a sensitive and efficient subtraction hybridization protocol for the identification of genes differentially regulated during the induction of differentiation in human melanoma cells."
Mol. Cell. Differ. 1:285-299(1993)

"The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells."
Oncogene 10:1855-1864(1995) [PubMed] [Europe PMC] [Abstract]

"Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen."
Exp. Cell Res. 211:90-98(1994) [PubMed] [Europe PMC] [Abstract]

"Two variants of the CIP1/WAF1 gene occur together and are associated with human cancer."
Hum. Mol. Genet. 4:1089-1092(1995) [PubMed] [Europe PMC] [Abstract]

"Human protein factory for converting the transcriptome into an in vitro-expressed proteome."
Nat. Methods 5:1011-1017(2008) [PubMed] [Europe PMC] [Abstract]

"The DNA sequence and analysis of human chromosome 6."
Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]

"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]

"N-acetylation and ubiquitin-independent proteasomal degradation of p21(Cip1)."
Mol. Cell 16:839-847(2004) [PubMed] [Europe PMC] [Abstract]

"Reversible phosphorylation at the C-terminal regulatory domain of p21(Waf1/Cip1) modulates proliferating cell nuclear antigen binding."
J. Biol. Chem. 275:11529-11537(2000) [PubMed] [Europe PMC] [Abstract]

"New functional activities for the p21 family of CDK inhibitors."
Genes Dev. 11:847-862(1997) [PubMed] [Europe PMC] [Abstract]

"A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome."
EMBO J. 20:2367-2375(2001) [PubMed] [Europe PMC] [Abstract]

"Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells."
Mol. Cell. Biol. 21:5644-5657(2001) [PubMed] [Europe PMC] [Abstract]

"Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase."
Biochim. Biophys. Acta 1593:45-55(2002) [PubMed] [Europe PMC] [Abstract]

"N-Terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome."
Mol. Cell. Biol. 24:6140-6150(2004) [PubMed] [Europe PMC] [Abstract]

"Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding."
Mol. Cell. Biol. 26:8267-8280(2006) [PubMed] [Europe PMC] [Abstract]

"A probability-based approach for high-throughput protein phosphorylation analysis and site localization."
Nat. Biotechnol. 24:1285-1292(2006) [PubMed] [Europe PMC] [Abstract]

"PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex."
Genes Dev. 22:2496-2506(2008) [PubMed] [Europe PMC] [Abstract]

"The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing."
Genes Dev. 22:2507-2519(2008) [PubMed] [Europe PMC] [Abstract]

"CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation."
J. Biol. Chem. 283:29045-29052(2008) [PubMed] [Europe PMC] [Abstract]

"A quantitative atlas of mitotic phosphorylation."
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]

"A dual role of Cdk2 in DNA damage response."
Cell Div. 4:9-9(2009) [PubMed] [Europe PMC] [Abstract]

"Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis."
EMBO J. 28:2100-2113(2009) [PubMed] [Europe PMC] [Abstract]

"Ionizing radiation induces ATM-independent degradation of p21Cip1 in transformed cells."
J. Biol. Chem. 284:15061-15070(2009) [PubMed] [Europe PMC] [Abstract]

"Pim-2 phosphorylation of p21(Cip1/WAF1) enhances its stability and inhibits cell proliferation in HCT116 cells."
Int. J. Biochem. Cell Biol. 42:1030-1038(2010) [PubMed] [Europe PMC] [Abstract]

"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]

"ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21(WAF1.)."
Cell Death Differ. 20:1055-1067(2013) [PubMed] [Europe PMC] [Abstract]

"A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation."
PLoS Genet. 10:E1004721-E1004721(2014) [PubMed] [Europe PMC] [Abstract]

"Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA."
Cell 87:297-306(1996) [PubMed] [Europe PMC] [Abstract]