Disease relevance of Cdkn1b

• But mice deficient for Cdkn1b (encoding p27(Kip1)) do not develop prostate cancer [1].
• Deletion of the gene encoding p27(Kip1) (Cdkn1b) ameliorated hyperglycemia in these animal models of type 2 diabetes mellitus by increasing islet mass and maintaining compensatory hyperinsulinemia, effects that were attributable predominantly to stimulation of pancreatic beta-cell proliferation [2].
• Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice [2].
• We show here that the adenovirus E1A oncoprotein prevents growth arrest by the CDK2 inhibitor p27(Kip1) (p27) in rodent fibroblasts [3].
• These included, for cyclin D1(-/-) mice, body weight, early lethality, retinal hypoplasia, and male aggressiveness and, for p27(-/-) mice, body weight, retinal hyperplasia, and embryo implantation. p27(-/-) traits that were not corrected were the aberrant estrus cycles, luteal cell proliferation, and susceptibility to pituitary tumors [4].
• Our study unveiled a previously unrecognized role for the control of p27 mRNA abundance in the development of non-small cell lung cancers [5].

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

• We also observed that hypoxia decreased p27 expression significantly in mouse lung, which was restored by heparin [9].
• Kip1 causes dioxin-induced suppression of 5L hepatoma cell proliferation because Kip1 antisense-expressing cells are resistant to dioxins [10].
• These results show that p27Kip1 is required for glucose-induced mesangial cell hypertrophy and cell cycle arrest [11].
• In the streptozotocin model of experimental diabetes in the mouse, glomerular hypertrophy was associated with a selective increase in p21 expression, whereas the levels of the CKI p27 and p57 did not change [12].
• CONCLUSION: Our findings are the first clear evidence that p27Kip1 is required for Ang II-induced hypertrophy of proximal tubular cells [13].

Biological context of Cdkn1b

• The murine gene Cdkn1b (p27(Kip1)) maps to distal chromosome 6 and is excluded as Pas1 [14].
• Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation [15].
• An increase in p27 causes proliferating cells to exit from the cell cycle, and a decrease in p27 is necessary for quiescent cells to resume division [16].
• Abnormally low amounts of p27 are associated with pathological states of excessive cell proliferation, especially cancers [16].
• The protein p27Kip1 is an inhibitor of cell division [16].

Anatomical context of Cdkn1b

• In mouse fibroblasts, p27 is associated predominantly with cyclin D1-Cdk4 [17].
• Mammary glands from p27(+/)- mice displayed increased ductal branching and proliferation with delayed postlactational involution [18].
• In contrast, p27(-/-) mammary glands or wild-type mammary fat pads reconstituted with p27(-/-) epithelium produced the opposite phenotype: hypoplasia, low proliferation, decreased ductal branching, impaired lobuloalveolar differentiation, and inability to lactate [18].
• Therefore, we studied the roles of p27 and cyclin D1 in ErbB2-mediated mammary epithelial cell transformation [19].
• These results suggest that the accumulation of p27 after DNA damage is required for suppression of centrosome amplification, thereby preventing chromosomal instability [20].

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

• Akt phosphorylates Thr-157 in p27 and retains it in the cytosol [31].
• We now show that cyclin E/cdk2 phosphorylates p27 at a carboxy-terminal threonine residue (T187) in vitro; mutation of this residue to valine stabilises cyclin E/cdk2 complexes [32].

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].

References