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Gene Review

Cdkn1b  -  cyclin-dependent kinase inhibitor 1B

Mus musculus

Synonyms: AA408329, AI843786, Cyclin-dependent kinase inhibitor 1B, Cyclin-dependent kinase inhibitor p27, Kip1, ...
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Disease relevance of Cdkn1b


High impact information on Cdkn1b

  • In response to receptor activation, betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300, resulting in enhanced local histone H4 acetylation and transcription of these genes [6].
  • Here we show that the concomitant inactivation of one Pten allele and one or both Cdkn1b alleles accelerates spontaneous neoplastic transformation and incidence of tumors of various histological origins [1].
  • Unexpectedly, the cell cycle arrest mediated by TGFbeta, rapamycin, or contact inhibition remained intact in p27(-/-) cells, suggesting that p27(Kip1) is not required in these pathways [7].
  • Growth is attributed to an increase in cell number, due to increased cell proliferation, most obviously in tissues that ordinarily express p27 at the highest levels [8].
  • Similar to mice with the Rb mutation, the p27(-/-) mice often develop pituitary tumors spontaneously [7].

Chemical compound and disease context of Cdkn1b


Biological context of Cdkn1b


Anatomical context of Cdkn1b


Associations of Cdkn1b with chemical compounds

  • To critically test the importance of this pathway in vivo, we replaced the murine p27 gene with one that encoded alanine instead of threonine at position 187 (p27T187A) [16].
  • Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1 [21].
  • Phosphorothioate p27 oligonucleotides decreased p27 protein in A431 cells and abrogated the quinazoline-mediated G(1) arrest [22].
  • Liver injury and repair were examined in wild type, p21Waf1/Cip1, and p27Kip1-deficient mice following carbon tetrachloride (CCl4) administration [23].
  • RESULTS: Insulin and IGF-I inhibited wild-type MC apoptosis induced by survival factor withdrawal, actinomycin D, ultraviolet-B irradiation and cycloheximide and in p27 -/- MC when apoptosis was induced by survival factor withdrawal [24].
  • We have found that p27 activates the caspase-9-caspase-3-caspase-7-poly (ADP-ribose) polymeraseapoptotic cascade by inhibiting Cdk2/Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia [25].

Physical interactions of Cdkn1b

  • Conditions that increased the abundance of the D cyclins also increased the abundance of enzymatically active D cyclin-cdk4 complexes in mouse embryo fibroblasts (MEFs) lacking both p27(Kip1) and p21(Cip1) (p27/p21(-/-)) [26].
  • Finally we found that the lack of kinase activity associated with cyclin E/cdk2 complexes was correlated with increased amounts of cdk2- and cyclin E-bound p27 [27].
  • The reduction in the expression of these genes correlates with the p27Kip1-induced accumulation of the repressor complexes of the E2F family of factors (E2Fs) [28].
  • These data argue that p27 can also cooperatively interact with p16 to inhibit DNA synthesis in hepatocytes [29].
  • Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes [30].

Enzymatic interactions of Cdkn1b


Regulatory relationships of Cdkn1b

  • Therefore, p27 is required for mammary gland development in a dose-dependent fashion and positively regulates cyclin D-Cdk4 function in the mammary gland [18].
  • Furthermore, p21 -/- MC apoptosis induced by survival factor withdrawal was not rescued by insulin in contrast to the wild-type and p27 -/- MC [24].
  • Functional assays showed that ectopic p27 expression can powerfully enhance the efficiency of MyoD-initiated muscle differentiation in cell culture [33].
  • In contrast, the amount of free p27 available to inhibit cyclin E/CDK2 is increased in E1A-expressing cells, owing to reduced expression of cyclins D1 and D3 [3].
  • Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels [34].
  • RNA interference-mediated depletion of cyclin D2 inhibited the nuclear export of p27 and delayed its degradation at the G(0)-G(1) transition [35].

Other interactions of Cdkn1b

  • p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21 [17].
  • Based on its ability to negatively regulate cyclin/Cdk function, loss of p27 may result in unrestrained cellular proliferation [18].
  • Cytokine treatment of irradiated cells induced Cdk2 phosphorylation and activation, and cells entered into S phase despite sustained high-level expression of p21 and p27 [36].
  • Jab1-/- embryonic cells, which lacked other CSN components, expressed higher levels of p27, p53, and cyclin E, resulting in impaired proliferation and accelerated apoptosis [37].
  • Jab1+/- mouse embryonic fibroblast cells, in which the amount of Jab1-containing small subcomplex, but not that of CSN, was selectively reduced, proliferated poorly, showed an inefficient down-regulation of p27 during G1, and was delayed in the progression from G0 to S phase by 3 h compared with the wild-type cells [37].
  • These results demonstrate that p27 carries out overlapping functions with p107 in controlling cell cycle exit during chondrocyte maturation [38].

Analytical, diagnostic and therapeutic context of Cdkn1b

  • Several tissues were highly sensitive to loss of p27 tumor suppressor function (intestine, adrenal, pituitary) resulting in an increased overall tumor burden in DKO mice compared to both wild-type (P<0.005) and Cx32-KO mice (P=0.066) [39].
  • Western blots of the known cdk inhibitors revealed proliferation-related decreases of p18, p21, and p27 from high expression in intact organs [40].
  • The goal of this study was to assess the role of p27 in the spatial, temporal, and conditional regulation of growth plate chondrocyte proliferation. p27 mRNA expression was detected by real-time RT-PCR in all zones of the mouse growth plate at levels approximately 2-fold lower than in the surrounding bone [41].
  • The levels of PCR products for cyclin D2, p27, and two forms of cdk2 were similar in meiotically incompetent and competent oocytes but decreased during oocyte maturation [42].
  • Modulating p27 expression in a small number of stem cells may translate into effects on the majority of mature cells, thereby providing a strategy for potentiating the impact of transduced cells in stem cell gene therapy [43].


  1. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C., Pandolfi, P.P. Nat. Genet. (2001) [Pubmed]
  2. Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Uchida, T., Nakamura, T., Hashimoto, N., Matsuda, T., Kotani, K., Sakaue, H., Kido, Y., Hayashi, Y., Nakayama, K.I., White, M.F., Kasuga, M. Nat. Med. (2005) [Pubmed]
  3. A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1). Alevizopoulos, K., Catarin, B., Vlach, J., Amati, B. EMBO J. (1998) [Pubmed]
  4. Genetic evidence for the interactions of cyclin D1 and p27(Kip1) in mice. Tong, W., Pollard, J.W. Mol. Cell. Biol. (2001) [Pubmed]
  5. Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. Timmerbeul, I., Garrett-Engele, C.M., Kossatz, U., Chen, X., Firpo, E., Grünwald, V., Kamino, K., Wilkens, L., Lehmann, U., Buer, J., Geffers, R., Kubicka, S., Manns, M.P., Porter, P.L., Roberts, J.M., Malek, N.P. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  6. A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Kang, J., Shi, Y., Xiang, B., Qu, B., Su, W., Zhu, M., Zhang, M., Bao, G., Wang, F., Zhang, X., Yang, R., Fan, F., Chen, X., Pei, G., Ma, L. Cell (2005) [Pubmed]
  7. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Nakayama, K., Ishida, N., Shirane, M., Inomata, A., Inoue, T., Shishido, N., Horii, I., Loh, D.Y., Nakayama, K. Cell (1996) [Pubmed]
  8. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Kiyokawa, H., Kineman, R.D., Manova-Todorova, K.O., Soares, V.C., Hoffman, E.S., Ono, M., Khanam, D., Hayday, A.C., Frohman, L.A., Koff, A. Cell (1996) [Pubmed]
  9. Cyclin-dependent kinase inhibitor p27Kip1, but not p21WAF1/Cip1, is required for inhibition of hypoxia-induced pulmonary hypertension and remodeling by heparin in mice. Yu, L., Quinn, D.A., Garg, H.G., Hales, C.A. Circ. Res. (2005) [Pubmed]
  10. p27(Kip1) induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells. Kolluri, S.K., Weiss, C., Koff, A., Göttlicher, M. Genes Dev. (1999) [Pubmed]
  11. High glucose-induced hypertrophy of mesangial cells requires p27(Kip1), an inhibitor of cyclin-dependent kinases. Wolf, G., Schroeder, R., Zahner, G., Stahl, R.A., Shankland, S.J. Am. J. Pathol. (2001) [Pubmed]
  12. The cyclin kinase inhibitor p21WAF1, CIP1 is increased in experimental diabetic nephropathy: potential role in glomerular hypertrophy. Kuan, C.J., al-Douahji, M., Shankland, S.J. J. Am. Soc. Nephrol. (1998) [Pubmed]
  13. Angiotensin II-induced hypertrophy of proximal tubular cells requires p27Kip1. Wolf, G., Jablonski, K., Schroeder, R., Reinking, R., Shankland, S.J., Stahl, R.A. Kidney Int. (2003) [Pubmed]
  14. The murine gene Cdkn1b (p27(Kip1)) maps to distal chromosome 6 and is excluded as Pas1. Kemp, C.J., Kim, K.H., Philipp, J. Mamm. Genome (2000) [Pubmed]
  15. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Kato, J.Y., Matsuoka, M., Polyak, K., Massagué, J., Sherr, C.J. Cell (1994) [Pubmed]
  16. A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Malek, N.P., Sundberg, H., McGrew, S., Nakayama, K., Kyriakides, T.R., Roberts, J.M., Kyriakidis, T.R. Nature (2001) [Pubmed]
  17. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Toyoshima, H., Hunter, T. Cell (1994) [Pubmed]
  18. Cyclin-dependent kinase inhibitor p27(Kip1) is required for mouse mammary gland morphogenesis and function. Muraoka, R.S., Lenferink, A.E., Simpson, J., Brantley, D.M., Roebuck, L.R., Yakes, F.M., Arteaga, C.L. J. Cell Biol. (2001) [Pubmed]
  19. ErbB2/Neu-induced, cyclin D1-dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells. Muraoka, R.S., Lenferink, A.E., Law, B., Hamilton, E., Brantley, D.M., Roebuck, L.R., Arteaga, C.L. Mol. Cell. Biol. (2002) [Pubmed]
  20. Suppression of centrosome amplification after DNA damage depends on p27 accumulation. Sugihara, E., Kanai, M., Saito, S., Nitta, T., Toyoshima, H., Nakayama, K., Nakayama, K.I., Fukasawa, K., Schwab, M., Saya, H., Miwa, M. Cancer Res. (2006) [Pubmed]
  21. Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1. Collado, M., Medema, R.H., Garcia-Cao, I., Dubuisson, M.L., Barradas, M., Glassford, J., Rivas, C., Burgering, B.M., Serrano, M., Lam, E.W. J. Biol. Chem. (2000) [Pubmed]
  22. Reversible G(1) arrest induced by inhibition of the epidermal growth factor receptor tyrosine kinase requires up-regulation of p27(KIP1) independent of MAPK activity. Busse, D., Doughty, R.S., Ramsey, T.T., Russell, W.E., Price, J.O., Flanagan, W.M., Shawver, L.K., Arteaga, C.L. J. Biol. Chem. (2000) [Pubmed]
  23. 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]
  24. Insulin is a potent survival factor in mesangial cells: role of the PI3-kinase/Akt pathway. Hiromura, K., Monkawa, T., Petermann, A.T., Durvasula, R.V., Shankland, S.J. Kidney Int. (2002) [Pubmed]
  25. p27kip1 (cyclin-dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice. Rajareddy, S., Reddy, P., Du, C., Liu, L., Jagarlamudi, K., Tang, W., Shen, Y., Berthet, C., Peng, S.L., Kaldis, P., Liu, K. Mol. Endocrinol. (2007) [Pubmed]
  26. 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]
  27. Effect of TGF-beta1 on cell cycle regulatory proteins in LPS-stimulated normal mouse B lymphocytes. Bouchard, C., Fridman, W.H., Sautès, C. J. Immunol. (1997) [Pubmed]
  28. p27Kip1 induces an accumulation of the repressor complexes of E2F and inhibits expression of the E2F-regulated genes. Shiyanov, P., Hayes, S., Chen, N., Pestov, D.G., Lau, L.F., Raychaudhuri, P. Mol. Biol. Cell (1997) [Pubmed]
  29. Hepatitis B virus X protein increases expression of p21(Cip-1/WAF1/MDA6) and p27(Kip-1) in primary mouse hepatocytes, leading to reduced cell cycle progression. Qiao, L., Leach, K., McKinstry, R., Gilfor, D., Yacoub, A., Park, J.S., Grant, S., Hylemon, P.B., Fisher, P.B., Dent, P. Hepatology (2001) [Pubmed]
  30. p27Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo. Soeiro, I., Mohamedali, A., Romanska, H.M., Lea, N.C., Child, E.S., Glassford, J., Orr, S.J., Roberts, C., Naresh, K.N., Lalani, e.l.-.N., Mann, D.J., Watson, R.J., Thomas, N.S., Lam, E.W. Mol. Cell. Biol. (2006) [Pubmed]
  31. Phosphorylation of p27Kip1 at Thr-157 interferes with its association with importin alpha during G1 and prevents nuclear re-entry. Shin, I., Rotty, J., Wu, F.Y., Arteaga, C.L. J. Biol. Chem. (2005) [Pubmed]
  32. Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes. Müller, D., Bouchard, C., Rudolph, B., Steiner, P., Stuckmann, I., Saffrich, R., Ansorge, W., Huttner, W., Eilers, M. Oncogene (1997) [Pubmed]
  33. p27Kip1 is expressed transiently in developing myotomes and enhances myogenesis. Zabludoff, S.D., Csete, M., Wagner, R., Yu, X., Wold, B.J. Cell Growth Differ. (1998) [Pubmed]
  34. Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels. Chandramohan, V., Jeay, S., Pianetti, S., Sonenshein, G.E. J. Immunol. (2004) [Pubmed]
  35. Cyclin D2 translocates p27 out of the nucleus and promotes its degradation at the G0-G1 transition. Susaki, E., Nakayama, K., Nakayama, K.I. Mol. Cell. Biol. (2007) [Pubmed]
  36. Dna damage-induced G(1) arrest in hematopoietic cells is overridden following phosphatidylinositol 3-kinase-dependent activation of cyclin-dependent kinase 2. Eapen, A.K., Henry, M.K., Quelle, D.E., Quelle, F.W. Mol. Cell. Biol. (2001) [Pubmed]
  37. Multiple functions of Jab1 are required for early embryonic development and growth potential in mice. Tomoda, K., Yoneda-Kato, N., Fukumoto, A., Yamanaka, S., Kato, J.Y. J. Biol. Chem. (2004) [Pubmed]
  38. Cooperation between p27 and p107 during endochondral ossification suggests a genetic pathway controlled by p27 and p130. Yeh, N., Miller, J.P., Gaur, T., Capellini, T.D., Nikolich-Zugich, J., de la Hoz, C., Selleri, L., Bromage, T.G., van Wijnen, A.J., Stein, G.S., Lian, J.B., Vidal, A., Koff, A. Mol. Cell. Biol. (2007) [Pubmed]
  39. Deficiency in the gap junction protein connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner. King, T.J., Gurley, K.E., Prunty, J., Shin, J.L., Kemp, C.J., Lampe, P.D. Oncogene (2005) [Pubmed]
  40. Unusual regulation of cyclin D1 and cyclin-dependent kinases cdk2 and cdk4 during in vivo mitotic stimulation of olfactory neuron progenitors in adult mouse. Kastner, A., Moyse, E., Bauer, S., Jourdan, F., Brun, G. J. Neurochem. (2000) [Pubmed]
  41. The role of p27Kip1 in the regulation of growth plate chondrocyte proliferation in mice. Emons, J.A., Marino, R., Nilsson, O., Barnes, K.M., Even-Zohar, N., Andrade, A.C., Chatterjee, N.A., Wit, J.M., Karperien, M., Baron, J. Pediatr. Res. (2006) [Pubmed]
  42. Temporal patterns of gene expression of G1-S cyclins and cdks during the first and second mitotic cell cycles in mouse embryos. Moore, G.D., Ayabe, T., Kopf, G.S., Schultz, R.M. Mol. Reprod. Dev. (1996) [Pubmed]
  43. Stem cell repopulation efficiency but not pool size is governed by p27(kip1). Cheng, T., Rodrigues, N., Dombkowski, D., Stier, S., Scadden, D.T. Nat. Med. (2000) [Pubmed]
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