Disease relevance of Cdkn1c

• The expression of p57Kip2 (Kip2), a cyclin-dependent kinase inhibitor that was also in the imprinted region, exhibited some variable increased expression predominantly in hepatic neoplasms from livers of female TG+ rats [1].
• METHODS: The expression of p57 protein in relation to markers of DNA synthesis was examined in developing mouse kidneys, and in the passive Heymann nephritis (PHN) and anti-glomerular antibody models of glomerular disease by immunohistochemistry [2].
• Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome [3].
• We have found that a cyclin kinase inhibitor, p57Kip2, is expressed in a restricted group of amacrine cells in the inner nuclear layer (INL) and ganglion cell layer (GCL) of the rodent retina [4].
• The conceptuses without p57Kip2 expression showed trophoblastic hyperplasia, which mimics the hallmark proliferation of intermediate trophoblasts in clinical preeclampsia [5].

High impact information on Cdkn1c

• p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin/Cdk complexes, and is a negative regulator of cell proliferation [6].
• Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse [6].
• The cyclin-dependent kinase inhibitor (CDKI), p21(cip1/waf1) (p21) dominates stem cell kinetics [7].
• Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development [8].
• Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution [9].

Biological context of Cdkn1c

• In addition, we find no evidence for allele-specific expression of p57(Kip2) (Cdkn1c) from our bacterial artificial chromosome transgenes that span 315 kb around the locus [10].
• Finally, we provide evidence for frequent de novo methylation of Cdkn1c in a variety of murine cancer types [11].
• Among these genes, we concentrated our study on the cell cycle regulators Cdkn1c and calcyclin and on the muscle-specific putative myogenic regulator Ankrd2 [12].
• Here, we demonstrate that there is a marked enhancement in postnatal viability of F(1) mice carrying either the ablated Igf2r ( approximately 32%) or Cdkn1c ( approximately 83%) when the paternal genome was derived from the inbred Mus musculus musculus CzechII/Ei strain [13].
• Domain regulation of imprinting cluster in Kip2/Lit1 subdomain on mouse chromosome 7F4/F5: large-scale DNA methylation analysis reveals that DMR-Lit1 is a putative imprinting control region [14].

Anatomical context of Cdkn1c

• The cyclin-dependent kinase inhibitors Cdkn1a and Cdkn1c are overexpressed in XX gonads at E11.5 and E12.5, suggesting that the increased proliferation of XY gonads relative to XX gonads may result from the overexpression of cell cycle inhibitors in the developing ovaries [15].
• To learn how ART might alter the epigenome, we examined morulas and blastocysts derived from C57BL/6J X M. spretus F1 mice conceived in vivo and in vitro and determined the allelic expression of four imprinted genes: Igf2, H19, Cdkn1c and Slc221L [16].
• Furthermore, we show that the maternally expressed Igf2r and p57KIP2 genes were repressed in the alleles of the non-growing oocyte indicating maternal modifications during oocyte growth are necessary for its expression [17].
• Cultured podocytes did not require changes in p57 protein levels to undergo differentiation [2].
• p57Kip2 expression is enhanced during mid-cardiac murine development and is restricted to trabecular myocardium [18].

Associations of Cdkn1c with chemical compounds

• Murine models have been used to study the effects of targeted deletions of the genes p57KIP2 and GPC3, as well as overexpression of IGF2 [19].
• Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby p57Kip2 influences postmitotic differentiation of dopamine neurons [20].
• Mutational deletion analysis showed that the NH2 terminal domain of p57Kip2 is necessary and sufficient to dimerization [21].
• These results indicate that thyroid hormone status affects p27(Kip1) expression in neonatal Sertoli cells, suggesting that T(3) effects on Sertoli cell proliferation may be mediated through this CDKI [22].
• In contrast to p27Kip1, the expression of p57Kip2 was not detected in the Dex-treated adrenal [23].

Regulatory relationships of Cdkn1c

• The Skp1/Cul1/F-box (SCF)-type E3 ubiquitin ligase complex SCFSkp2 has now been shown to be responsible for regulating the cellular level of p57Kip2 by targeting it for ubiquitylation and proteolysis [24].
• Dimerization of the amino terminal domain of p57Kip2 inhibits cyclin D1-cdk4 kinase activity [21].

Other interactions of Cdkn1c

• Different causes, such as maternal diabetes, cloning by nuclear transfer, interspecific hybridization, and deletion of some genes such as Esx1, Ipl, or Cdkn1c, may underlie placental overgrowth [25].
• This was diffuse in PHN, whereas in the murine model, loss of expression of p57 occurred predominantly in proliferating podocytes, expressing proliferating cell nuclear antigen (PCNA) [2].
• In Splotch embryos, expression of p57Kip2 is expanded to encompass the entire thickness of the myocardium [18].
• For the maternally expressed p57Kip2 gene, passage through the female germline is essential to generate the active state, whereas passage through the male germline is needed to force the maternally expressed H19 gene into an inactive state [26].
• Whereas the expression of p57Kip2 in most tissues was restricted to embryogenesis, expression of p27Kip1 in many tissues was maintained in adult animals [27].

Analytical, diagnostic and therapeutic context of Cdkn1c

• Chromatin immunoprecipitations demonstrate a direct association of Lsh with the 5' DMR at the Cdkn1c promoter, but not with Kv DMR1 or other imprinted loci [28].
• There was a marked decrease in p57 expression in both animal models of podocyte injury [2].
• A synchronized wave of basal keratinocyte proliferation occurred; over 80% of the cells were in S phase 15 h after treatment. c-myc protein expression was induced, and p57Kip2 protein levels dropped early after stimulation [29].
• Here we show, using fluorescence in situ hybridization (FISH) analysis, that the large chromosomal domain of the mouse distal chromosome 7 imprinting cluster, approximately 1 Mb in length between p57Kip2 and H19 genes, replicates asynchronously between the two alleles during S-phase [30].
• Cyclin dependent protein kinase (Cdk) inhibitor (CDKI) activity assays were done to determine the expression/activities of Cdks and Western blot analysis was performed to determine the presence of CDKIs and other cell cycle regulator proteins [31].

References