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Gene Review

Cdkn1a  -  cyclin-dependent kinase inhibitor 1A (P21)

Mus musculus

Synonyms: CAP20, CDK-interacting protein 1, CDKI, CIP1, Cdkn1, ...
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Disease relevance of Cdkn1a

  • Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction [1].
  • We report here that, similarly to loss of p53, disruption of the p21(WAF1/Cip1) gene results in a markedly increased susceptibility to chemically induced skin carcinoma formation, whereas the number of papillomas is reduced [2].
  • It was recently reported that the p53-independent elevation of p21 protein levels is essential in mediating the G(1) arrest resulting from signal transduction events initiated by the crosslinking of membrane IgM on Daudi Burkitt lymphoma cells [3].
  • In contrast, higher and sustained levels of proliferation, resulting in myofibroblast hyperplasia and monocytic inflammation, occurred in recovered p21-deficient lungs [4].
  • We found that inactivation of p21(WAF1/cip1) significantly increased the frequency and size of intestinal tumors in Muc2 knockout mice and also led to development of more invasive adenocarcinomas [5].

Psychiatry related information on Cdkn1a

  • In cell extracts, we found that complementary strand synthesis was inhibited by the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and rescued by the addition of proliferating cell nuclear antigen, arguing for the involvement of DNA polymerase (Pol) delta in the conversion reaction [6].
  • Thus, p21 deficiency significantly enhances T cell activation and homeostatic proliferation, and can induce mild autoimmune manifestations at a low incidence without gender bias, but does not in itself generate the full spectrum of lupus-like disease [7].
  • We investigated the development of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in AVCN neurons using whole cell patch-clamp techniques during [postnatal day 7 (P7)] and after (P14, P21) this critical period [8].
  • Motor coordination was assessed by locomotor activity evaluation of control and experimental pups at P14, P21 and P30 [9].

High impact information on Cdkn1a

  • Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation [10].
  • Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres [10].
  • In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation [10].
  • Smad proteins activated by TGF-beta form a complex with FoxO proteins to turn on the growth inhibitory gene p21Cip1 [11].
  • p53-mediated increase in cyclin-dependent kinase inhibitor p21(WAF1) protein is thought to be the major mediator of cell cycle arrest after DNA damage [12].

Chemical compound and disease context of Cdkn1a


Biological context of Cdkn1a


Anatomical context of Cdkn1a


Associations of Cdkn1a with chemical compounds

  • Induction of Cdkn1a expression was transient, reaching maximal levels in the CNS 3-6 h after LPS administration, and returning to untreated levels by 24 h [22].
  • Cell proliferation was measured by bromodeoxyuridine incorporation following p21(waf1/cip1) silencing with RNAi [25].
  • Moreover, p21 is required to a similar extent to maintain cell cycle arrest after either nocodazole treatment or irradiation [26].
  • These findings suggest that basal expression of p21 plays a facilitating, proapoptotic role in DCA-induced apoptosis [27].
  • Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor [28].

Physical interactions of Cdkn1a


Enzymatic interactions of Cdkn1a


Regulatory relationships of Cdkn1a

  • Inactivation of p53 in c-jun (Deltali*) mice abrogated both hepatocyte cell cycle block and increased p21 protein expression [35].
  • Surprisingly, p21Waf-1/Cip-1 is induced in the sensory ganglia of Rb-mutant embryos in a p53-independent manner [36].
  • The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot [37].
  • The same element is also required by p53 to activate the p21(WAF1/Cip1) promoter, although p53 does not bind to it [38].
  • Inactivation of p21WAF1/cip1 enhances intestinal tumor formation in Muc2-/- mice [5].
  • The absence of p21 significantly impaired the enhanced p53-mediated cell-cycle arrest characteristic of super-p53 cells, but did not affect the enhanced apoptosis [39].
  • Disruption of SDF-1/CXCR4 signaling inhibited the proliferative response during vascular remodeling in both p21+/+ and p21-/- mice [40].
  • Biochemical and genetic data show that oscillation of p21WAF1/CIP1 gene transcription is regulated by the antagonistic activities of the orphan nuclear receptors REV-ERBalpha/beta and RORalpha4/gamma, which are core clock regulators [41].

Other interactions of Cdkn1a


Analytical, diagnostic and therapeutic context of Cdkn1a


  1. Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity. Lawson, B.R., Baccala, R., Song, J., Croft, M., Kono, D.H., Theofilopoulos, A.N. J. Exp. Med. (2004) [Pubmed]
  2. p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. Topley, G.I., Okuyama, R., Gonzales, J.G., Conti, C., Dotto, G.P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. Cancer dormancy and cell signaling: induction of p21(waf1) initiated by membrane IgM engagement increases survival of B lymphoma cells. Marches, R., Hsueh, R., Uhr, J.W. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  4. Normal remodeling of the oxygen-injured lung requires the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1). Staversky, R.J., Watkins, R.H., Wright, T.W., Hernady, E., LoMonaco, M.B., D'Angio, C.T., Williams, J.P., Maniscalco, W.M., O'Reilly, M.A. Am. J. Pathol. (2002) [Pubmed]
  5. Inactivation of p21WAF1/cip1 enhances intestinal tumor formation in Muc2-/- mice. Yang, W., Velcich, A., Lozonschi, I., Liang, J., Nicholas, C., Zhuang, M., Bancroft, L., Augenlicht, L.H. Am. J. Pathol. (2005) [Pubmed]
  6. Cyclin A activates the DNA polymerase delta -dependent elongation machinery in vitro: A parvovirus DNA replication model. Bashir, T., Horlein, R., Rommelaere, J., Willwand, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  7. Role of cyclin kinase inhibitor p21 in systemic autoimmunity. Santiago-Raber, M.L., Lawson, B.R., Dummer, W., Barnhouse, M., Koundouris, S., Wilson, C.B., Kono, D.H., Theofilopoulos, A.N. J. Immunol. (2001) [Pubmed]
  8. Development of Spontaneous Miniature EPSCs in Mouse AVCN Neurons During a Critical Period of Afferent-Dependent Neuron Survival. Lu, Y., Harris, J.A., Rubel, E.W. J. Neurophysiol. (2007) [Pubmed]
  9. Effects of prenatal paraquat and mancozeb exposure on amino acid synaptic transmission in developing mouse cerebellar cortex. Miranda-Contreras, L., Dávila-Ovalles, R., Benítez-Díaz, P., Peña-Contreras, Z., Palacios-Prü, E. Brain Res. Dev. Brain Res. (2005) [Pubmed]
  10. 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]
  11. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Seoane, J., Le, H.V., Shen, L., Anderson, S.A., Massagué, J. Cell (2004) [Pubmed]
  12. UV irradiation triggers ubiquitin-dependent degradation of p21(WAF1) to promote DNA repair. Bendjennat, M., Boulaire, J., Jascur, T., Brickner, H., Barbier, V., Sarasin, A., Fotedar, A., Fotedar, R. Cell (2003) [Pubmed]
  13. Induction and bypass of p53 during productive infection by polyomavirus. Dey, D., Dahl, J., Cho, S., Benjamin, T.L. J. Virol. (2002) [Pubmed]
  14. Lack of a functional p21WAF1/CIP1 gene accelerates caspase-independent apoptosis induced by cisplatin in renal cells. Nowak, G., Price, P.M., Schnellmann, R.G. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  15. The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy. Al-Douahji, M., Brugarolas, J., Brown, P.A., Stehman-Breen, C.O., Alpers, C.E., Shankland, S.J. Kidney Int. (1999) [Pubmed]
  16. 1,25-Dihydroxycholecalciferol (1,25-D3) inhibits the growth of squamous cell carcinoma and down-modulates p21(Waf1/Cip1) in vitro and in vivo. Hershberger, P.A., Modzelewski, R.A., Shurin, Z.R., Rueger, R.M., Trump, D.L., Johnson, C.S. Cancer Res. (1999) [Pubmed]
  17. Increased resistance of the radiosensitive M10 mutant cells of the L5178Y mouse lymphoma cell line to heat-induced apoptosis. Ostapenko, V.V., Wang, X., Ohnishi, K., Takahashi, A., Yamamoto, I., Tanaka, Y., Ohnishi, T. Radiat. Res. (1999) [Pubmed]
  18. The neoplastic transformation of SCID cells by radiation. Lun, M., Wells, R.L., Lang, S., Chawapun, N., Elkind, M.M. Radiat. Res. (1999) [Pubmed]
  19. Genomic instability in Gadd45a-/- cells is coupled with S-phase checkpoint defects. Hollander, M.C., Philburn, R.T., Patterson, A.D., Wyatt, M.A., Fornace, A.J. Cell Cycle (2005) [Pubmed]
  20. Radiation-induced cell cycle arrest compromised by p21 deficiency. Brugarolas, J., Chandrasekaran, C., Gordon, J.I., Beach, D., Jacks, T., Hannon, G.J. Nature (1995) [Pubmed]
  21. Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity. Woo, M., Hakem, R., Furlonger, C., Hakem, A., Duncan, G.S., Sasaki, T., Bouchard, D., Lu, L., Wu, G.E., Paige, C.J., Mak, T.W. Nat. Immunol. (2003) [Pubmed]
  22. The Cdkn1a gene (p21Waf1/Cip1) is an inflammatory response gene in the mouse central nervous system. Ring, R.H., Valo, Z., Gao, C., Barish, M.E., Singer-Sam, J. Neurosci. Lett. (2003) [Pubmed]
  23. p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Parker, S.B., Eichele, G., Zhang, P., Rawls, A., Sands, A.T., Bradley, A., Olson, E.N., Harper, J.W., Elledge, S.J. Science (1995) [Pubmed]
  24. Targeted in vivo expression of the cyclin-dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development and regeneration. Wu, H., Wade, M., Krall, L., Grisham, J., Xiong, Y., Van Dyke, T. Genes Dev. (1996) [Pubmed]
  25. Epidermal growth factor receptor-mediated proliferation of enterocytes requires p21waf1/cip1 expression. Sheng, G., Bernabe, K.Q., Guo, J., Warner, B.W. Gastroenterology (2006) [Pubmed]
  26. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Lanni, J.S., Jacks, T. Mol. Cell. Biol. (1998) [Pubmed]
  27. Cyclin kinase inhibitor p21 potentiates bile acid-induced apoptosis in hepatocytes that is dependent on p53. Qiao, L., McKinstry, R., Gupta, S., Gilfor, D., Windle, J.J., Hylemon, P.B., Grant, S., Fisher, P.B., Dent, P. Hepatology (2002) [Pubmed]
  28. Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor. Iurisci, I., Filipski, E., Reinhardt, J., Bach, S., Gianella-Borradori, A., Iacobelli, S., Meijer, L., L??vi, F. Cancer Res. (2006) [Pubmed]
  29. UV radiation is a transcriptional inducer of p21(Cip1/Waf1) cyclin-kinase inhibitor in a p53-independent manner. Haapajärvi, T., Kivinen, L., Heiskanen, A., des Bordes, C., Datto, M.B., Wang, X.F., Laiho, M. Exp. Cell Res. (1999) [Pubmed]
  30. P27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes. Bagui, T.K., Mohapatra, S., Haura, E., Pledger, W.J. Mol. Cell. Biol. (2003) [Pubmed]
  31. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. Bornstein, G., Bloom, J., Sitry-Shevah, D., Nakayama, K., Pagano, M., Hershko, A. J. Biol. Chem. (2003) [Pubmed]
  32. Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites. Kivinen, L., Tsubari, M., Haapajärvi, T., Datto, M.B., Wang, X.F., Laiho, M. Oncogene (1999) [Pubmed]
  33. Site-directed mutant p21 proteins defective in both inhibition of E2F-regulated transcription and disruption of E2F-p130-cyclin-cdk2 complexes. Robles, S.J., Shiyanov, P., Aristodemo, G.T., Raychaudhuri, P., Adami, G.R. DNA Cell Biol. (1998) [Pubmed]
  34. The Cdk inhibitor p21 is required for necrosis, but it inhibits apoptosis following toxin-induced liver injury. Kwon, Y.H., Jovanovic, A., Serfas, M.S., Tyner, A.L. J. Biol. Chem. (2003) [Pubmed]
  35. c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Stepniak, E., Ricci, R., Eferl, R., Sumara, G., Sumara, I., Rath, M., Hui, L., Wagner, E.F. Genes Dev. (2006) [Pubmed]
  36. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. Macleod, K.F., Hu, Y., Jacks, T. EMBO J. (1996) [Pubmed]
  37. The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Jernvall, J., Aberg, T., Kettunen, P., Keränen, S., Thesleff, I. Development (1998) [Pubmed]
  38. The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/Cip1 promoter. Zhang, W., Geiman, D.E., Shields, J.M., Dang, D.T., Mahatan, C.S., Kaestner, K.H., Biggs, J.R., Kraft, A.S., Yang, V.W. J. Biol. Chem. (2000) [Pubmed]
  39. Genetic dissection of the role of p21Cip1/Waf1 in p53-mediated tumour suppression. Efeyan, A., Collado, M., Velasco-Miguel, S., Serrano, M. Oncogene (2007) [Pubmed]
  40. p21Cip1 modulates arterial wound repair through the stromal cell-derived factor-1/CXCR4 axis in mice. Olive, M., Mellad, J.A., Beltran, L.E., Ma, M., Cimato, T., Noguchi, A.C., San, H., Childs, R., Kovacic, J.C., Boehm, M. J. Clin. Invest. (2008) [Pubmed]
  41. The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation. Gréchez-Cassiau, A., Rayet, B., Guillaumond, F., Teboul, M., Delaunay, F. J. Biol. Chem. (2008) [Pubmed]
  42. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Devgan, V., Mammucari, C., Millar, S.E., Brisken, C., Dotto, G.P. Genes Dev. (2005) [Pubmed]
  43. p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Smith, M.L., Ford, J.M., Hollander, M.C., Bortnick, R.A., Amundson, S.A., Seo, Y.R., Deng, C.X., Hanawalt, P.C., Fornace, A.J. Mol. Cell. Biol. (2000) [Pubmed]
  44. Molecular cloning, sequencing, chromosomal localization and expression of mouse p21 (Waf1). Huppi, K., Siwarski, D., Dosik, J., Michieli, P., Chedid, M., Reed, S., Mock, B., Givol, D., Mushinski, J.F. Oncogene (1994) [Pubmed]
  45. Inhibin and p27 interact to regulate gonadal tumorigenesis. Cipriano, S.C., Chen, L., Burns, K.H., Koff, A., Matzuk, M.M. Mol. Endocrinol. (2001) [Pubmed]
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