The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

CDKN1A  -  cyclin-dependent kinase inhibitor 1A (p21,...

Homo sapiens

Synonyms: CAP20, CDK-interacting protein 1, CDKN1, CIP1, Cyclin-dependent kinase inhibitor 1, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of CDKN1A

  • These results suggest that in a European-American population, CDKN1A and CDKN1B variants are associated with advanced prostate cancer [1].
  • Three genes - CDKN1A, DDB2 and ADRB2 - exhibited a trend towards loss of expression in melanomas thereby raising the possibility of a linked role in tumorigenesis [2].
  • GADD45-alpha and CDKN1A protein levels were related to each other both in cirrhotic and in neoplastic tissues, and a concordant up- or down-regulation was observed in HCCs with respect to cirrhosis [3].
  • The relative induction of genes such as CDKN1A by radiation doses that produce little toxicity indicates that surviving cells do contribute significantly to the observed stress responses [4].
  • These results suggest that glycerol is effective in restoring several TP53 mutants to normal TP53 function, leading to normal CDKN1A expression after heat stress [5].

Psychiatry related information on CDKN1A


High impact information on CDKN1A


Chemical compound and disease context of CDKN1A


Biological context of CDKN1A

  • Our results indicate that alpha particle-associated increases in cell growth correlate with intracellular increases in ROS along with decreases in TP53 and CDKN1A, and that these cellular responses are mechanistically coupled [17].
  • CDKN1A genotype was scored as CC, CT, and TT on the basis of the digestion products [1].
  • Like the increased intracellular ROS bystander effect, this "decreased TP53/CDKN1A response" can be mimicked in otherwise untreated cells by the addition of low concentrations of TGF-beta1 [17].
  • Taken together, these results strongly suggest that increased expression of p21/CDKN1A is necessary and sufficient for the negative regulation of gene expression by p53 [18].
  • Tbx2 is a transcriptional repressor implicated in several developmental processes and which has also been implicated in cancer through its ability to suppress senescence via repression of the p19(ARF) and p21(Cip1) (CDKN1A) promoters [19].

Anatomical context of CDKN1A


Associations of CDKN1A with chemical compounds

  • These associations were particularly strong in those patients with androgen-independent disease [OR = 2.88 (95% CI, 1.19-6.97) and 2.11 (95% CI, 1.05-4.22) for high-risk genotypes of CDKN1A and CDKN1B, respectively] [1].
  • These cells showed similar CDKN1A expression when heated in the presence of glycerol at 0.6 or 1.2 M [5].
  • The strongly 5-FU-resistant ContinD cell line had the smallest S phase arrests, the lowest CDKN1A levels, and the lowest levels of 5-FU-induced apoptosis throughout the treatment and recovery periods, and the fastest recovery of exponential growth (10 days) compared to the other two cell lines [24].
  • Our data suggest that p53 acetylation at K373/K382 plays an important role in depsipeptide-induced p21(Waf1/Cip1) expression [25].
  • The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel [13].
  • These data show that p21 is a potential and novel molecular target for RXR ligand-mediated anti-cancer therapy and that the expression level of retinoic acid receptor and RXR in tumors may be crucial to induce p21-mediated cell growth arrest in RXR ligand therapy [26].

Physical interactions of CDKN1A

  • Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA [27].
  • Dephosphorylation on Y15 and phosphorylation on T161 promotes Cdc2 binding to the p21-cyclin B1 complex, which becomes activated as a kinase [28].
  • Phosphorylated p21 binds to cyclin B1 when Cdc2 is phosphorylated on Y15 and associates poorly with the complex [28].
  • Furthermore, UCN-01 induced the expression of the CDK inhibitor p21 protein and its complex formation with CDK2 after 24 h exposure at 260 and 520 nM, whereas the expression level was very low or undetectable in untreated or DNA-damaged cells [29].
  • We found that the distal p53-binding site of the p21 promoter acts as an enhancer on the homologous or heterologous promoters in hepatoma HepG2 cells [30].

Enzymatic interactions of CDKN1A

  • S126-phosphorylated cyclin B1 binds to T57-phosphorylated p21 [28].
  • While ubiquitination of PCNA was not affected by deficient nucleotide excision repair (NER) and was observed in both proliferating and arrested cells, stable p21 expression caused a significant reduction in UV-induced ubiquitinated PCNA [31].
  • During in vitro studies, purified p21 was cleaved by PR3, resulting in a 10-kDa p21 fragment [32].
  • We report herein that p21 was cleaved by caspase-3/CPP32 at the site of DHVD112L during the DNA damage-induced apoptosis of cancer cells [33].
  • Proteolytic processing was the result of caspase-3 activity, which accompanied the early changes in cell morphology and DNA fragmentation. p21WAF1/CIP1 translated in vitro was cleaved into a p14 fragment when incubated with cell extracts obtained from either ginsenoside Rh2-treated or staurosporine-treated cells [34].

Co-localisations of CDKN1A


Regulatory relationships of CDKN1A

  • The p53 tumour-suppressor protein controls the expression of a gene encoding the p21 cyclin-dependent protein kinase (CDK) regulator [36].
  • Thus, hyperphosphorylated p21 activates the Cdc2 kinase in the G2/M transition [28].
  • A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the dephosphorylation of the kinase. p21 inhibits Cdc25A-cyclin-cdk2 association and the dephosphorylation of cdk2 [37].
  • Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity [28].
  • p21WAF1/CIP1 selectively controls the transcriptional activity of estrogen receptor alpha [38].
  • We found that RNPC1a is required to maintain the stability of p21 transcript induced by p53 [39].

Other interactions of CDKN1A

  • Upon activation of the ATR-intra-S phase checkpoint, Deltap53, but not p53, transactivates the Cdk inhibitor p21 [40].
  • An intact trimeric ring is maintained in the structure of the p21-PCNA complex, with a central hole available for DNA interaction [27].
  • Taken together, our results demonstrate that p21Cip1/WAF1 is an important mediator of EGF-induced G1 arrest and growth inhibition in A431 cells [41].
  • Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts [42].
  • Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity [43].
  • Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 ubiquitin ligase complex [44].

Analytical, diagnostic and therapeutic context of CDKN1A


  1. CDKN1A and CDKN1B polymorphisms and risk of advanced prostate carcinoma. Kibel, A.S., Suarez, B.K., Belani, J., Oh, J., Webster, R., Brophy-Ebbers, M., Guo, C., Catalona, W.J., Picus, J., Goodfellow, P.J. Cancer Res. (2003) [Pubmed]
  2. Expression Profiling of UVB Response in Melanocytes Identifies a Set of p53-Target Genes. Yang, G., Zhang, G., Pittelkow, M.R., Ramoni, M., Tsao, H. J. Invest. Dermatol. (2006) [Pubmed]
  3. GADD45-alpha expression in cirrhosis and hepatocellular carcinoma: relationship with DNA repair and proliferation. Gramantieri, L., Chieco, P., Giovannini, C., Lacchini, M., Treré, D., Grazi, G.L., Venturi, A., Bolondi, L. Hum. Pathol. (2005) [Pubmed]
  4. Induction of stress genes by low doses of gamma rays. Amundson, S.A., Do, K.T., Fornace, A.J. Radiat. Res. (1999) [Pubmed]
  5. Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone. Ohnishi, T., Ohnishi, K., Wang, X., Takahashi, A., Okaichi, K. Radiat. Res. (1999) [Pubmed]
  6. The role of cyclin D2 and p21/waf1 in human T-cell leukemia virus type 1 infected cells. Kehn, K., Deng, L., de la Fuente, C., Strouss, K., Wu, K., Maddukuri, A., Baylor, S., Rufner, R., Pumfery, A., Bottazzi, M.E., Kashanchi, F. Retrovirology (2004) [Pubmed]
  7. Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer's disease. Arendt, T., Holzer, M., Gärtner, U. Journal of neural transmission (Vienna, Austria : 1996) (1998) [Pubmed]
  8. Cell cycle blockade and differentiation of ovarian cancer cells by the histone deacetylase inhibitor trichostatin A are associated with changes in p21, Rb, and Id proteins. Strait, K.A., Dabbas, B., Hammond, E.H., Warnick, C.T., Iistrup, S.J., Ford, C.D. Mol. Cancer Ther. (2002) [Pubmed]
  9. Another Piece of the p27(Kip1) Puzzle. Kaldis, P. Cell (2007) [Pubmed]
  10. Telomeres, p21 and the cancer-aging hypothesis. Bell, J.F., Sharpless, N.E. Nat. Genet. (2007) [Pubmed]
  11. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Choudhury, A.R., Ju, Z., Djojosubroto, M.W., Schienke, A., Lechel, A., Schaetzlein, S., Jiang, H., Stepczynska, A., Wang, C., Buer, J., Lee, H.W., von Zglinicki, T., Ganser, A., Schirmacher, P., Nakauchi, H., Rudolph, K.L. Nat. Genet. (2007) [Pubmed]
  12. Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. Cariou, S., Donovan, J.C., Flanagan, W.M., Milic, A., Bhattacharya, N., Slingerland, J.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  13. The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel. Mitsuuchi, Y., Johnson, S.W., Selvakumaran, M., Williams, S.J., Hamilton, T.C., Testa, J.R. Cancer Res. (2000) [Pubmed]
  14. Involvement of p21(WAF1/Cip1), p27(Kip1), and p18(INK4c) in troglitazone-induced cell-cycle arrest in human hepatoma cell lines. Koga, H., Sakisaka, S., Harada, M., Takagi, T., Hanada, S., Taniguchi, E., Kawaguchi, T., Sasatomi, K., Kimura, R., Hashimoto, O., Ueno, T., Yano, H., Kojiro, M., Sata, M. Hepatology (2001) [Pubmed]
  15. Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm. Yang, E.S., Burnstein, K.L. J. Biol. Chem. (2003) [Pubmed]
  16. Induction of p21 mediated by reactive oxygen species formed during the metabolism of aziridinylbenzoquinones by HCT116 cells. Qiu, X., Forman, H.J., Schönthal, A.H., Cadenas, E. J. Biol. Chem. (1996) [Pubmed]
  17. Factors underlying the cell growth-related bystander responses to alpha particles. Iyer, R., Lehnert, B.E., Svensson, R. Cancer Res. (2000) [Pubmed]
  18. p21/CDKN1A mediates negative regulation of transcription by p53. Löhr, K., Möritz, C., Contente, A., Dobbelstein, M. J. Biol. Chem. (2003) [Pubmed]
  19. Cell cycle regulation of the T-box transcription factor tbx2. Bilican, B., Goding, C.R. Exp. Cell Res. (2006) [Pubmed]
  20. Induction of accelerated senescence by gamma radiation in human solid tumor-derived cell lines expressing wild-type TP53. Mirzayans, R., Scott, A., Cameron, M., Murray, D. Radiat. Res. (2005) [Pubmed]
  21. Characterization of CDKN1A (p21) binding to sites of heavy-ion-induced damage: colocalization with proteins involved in DNA repair. Jakob, B., Scholz, M., Taucher-Scholz, G. Int. J. Radiat. Biol. (2002) [Pubmed]
  22. p21+/+ (CDKN1A+/+) and p21-/- (CDKN1A-/-) human colorectal carcinoma cells display equivalent amounts of thermal radiosensitization. Larsson, C., Ng, C.E. Radiat. Res. (2003) [Pubmed]
  23. Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles. Azzam, E.I., de Toledo, S.M., Gooding, T., Little, J.B. Radiat. Res. (1998) [Pubmed]
  24. Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. De Angelis, P.M., Svendsrud, D.H., Kravik, K.L., Stokke, T. Mol. Cancer (2006) [Pubmed]
  25. Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Zhao, Y., Lu, S., Wu, L., Chai, G., Wang, H., Chen, Y., Sun, J., Yu, Y., Zhou, W., Zheng, Q., Wu, M., Otterson, G.A., Zhu, W.G. Mol. Cell. Biol. (2006) [Pubmed]
  26. p21WAF1/CIP1 is a common transcriptional target of retinoid receptors: pleiotropic regulatory mechanism through retinoic acid receptor (RAR)/retinoid X receptor (RXR) heterodimer and RXR/RXR homodimer. Tanaka, T., Suh, K.S., Lo, A.M., De Luca, L.M. J. Biol. Chem. (2007) [Pubmed]
  27. Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA. Gulbis, J.M., Kelman, Z., Hurwitz, J., O'Donnell, M., Kuriyan, J. Cell (1996) [Pubmed]
  28. Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. Dash, B.C., El-Deiry, W.S. Mol. Cell. Biol. (2005) [Pubmed]
  29. G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/Sdi1 in p53-mutated human epidermoid carcinoma A431 cells. Akiyama, T., Yoshida, T., Tsujita, T., Shimizu, M., Mizukami, T., Okabe, M., Akinaga, S. Cancer Res. (1997) [Pubmed]
  30. Sp1 plays a critical role in the transcriptional activation of the human cyclin-dependent kinase inhibitor p21(WAF1/Cip1) gene by the p53 tumor suppressor protein. Koutsodontis, G., Tentes, I., Papakosta, P., Moustakas, A., Kardassis, D. J. Biol. Chem. (2001) [Pubmed]
  31. P21Cip1/WAF1 downregulation is required for efficient PCNA ubiquitination after UV irradiation. Soria, G., Podhajcer, O., Prives, C., Gottifredi, V. Oncogene (2006) [Pubmed]
  32. Cleavage of p21waf1 by proteinase-3, a myeloid-specific serine protease, potentiates cell proliferation. Witko-Sarsat, V., Canteloup, S., Durant, S., Desdouets, C., Chabernaud, R., Lemarchand, P., Descamps-Latscha, B. J. Biol. Chem. (2002) [Pubmed]
  33. Caspase-mediated cleavage of p21Waf1/Cip1 converts cancer cells from growth arrest to undergoing apoptosis. Zhang, Y., Fujita, N., Tsuruo, T. Oncogene (1999) [Pubmed]
  34. Caspase 3 specifically cleaves p21WAF1/CIP1 in the earlier stage of apoptosis in SK-HEP-1 human hepatoma cells. Park, J.A., Kim, K.W., Kim, S.I., Lee, S.K. Eur. J. Biochem. (1998) [Pubmed]
  35. In human hepatocellular carcinoma in cirrhosis proliferating cell nuclear antigen (PCNA) is involved in cell proliferation and cooperates with P21 in DNA repair. Gramantieri, L., Trerè, D., Chieco, P., Lacchini, M., Giovannini, C., Piscaglia, F., Cavallari, A., Bolondi, L. J. Hepatol. (2003) [Pubmed]
  36. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Waga, S., Hannon, G.J., Beach, D., Stillman, B. Nature (1994) [Pubmed]
  37. p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases. Saha, P., Eichbaum, Q., Silberman, E.D., Mayer, B.J., Dutta, A. Mol. Cell. Biol. (1997) [Pubmed]
  38. p21WAF1/CIP1 selectively controls the transcriptional activity of estrogen receptor alpha. Fritah, A., Saucier, C., Mester, J., Redeuilh, G., Sabbah, M. Mol. Cell. Biol. (2005) [Pubmed]
  39. RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript. Shu, L., Yan, W., Chen, X. Genes Dev. (2006) [Pubmed]
  40. A novel human p53 isoform is an essential element of the ATR-intra-S phase checkpoint. Rohaly, G., Chemnitz, J., Dehde, S., Nunez, A.M., Heukeshoven, J., Deppert, W., Dornreiter, I. Cell (2005) [Pubmed]
  41. Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition. Fan, Z., Lu, Y., Wu, X., DeBlasio, A., Koff, A., Mendelsohn, J. J. Cell Biol. (1995) [Pubmed]
  42. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Alcorta, D.A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., Barrett, J.C. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  43. Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. Kriwacki, R.W., Hengst, L., Tennant, L., Reed, S.I., Wright, P.E. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  44. PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Abbas, T., Sivaprasad, U., Terai, K., Amador, V., Pagano, M., Dutta, A. Genes Dev. (2008) [Pubmed]
  45. Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts. Bani, M.R., Nicoletti, M.I., Alkharouf, N.W., Ghilardi, C., Petersen, D., Erba, E., Sausville, E.A., Liu, E.T., Giavazzi, R. Mol. Cancer Ther. (2004) [Pubmed]
WikiGenes - Universities