Disease relevance of CDKN1C

• Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth disorder involving the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15 [1].
• The 11p15 LOH and absence of CDKN1C peptide staining are demonstrated in all FoPHHI but also in three of eight insulinomas [2].
• Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer [3].
• Furthermore, a subset of pancreatic cancers showed complete hypomethylation of LIT1, an imprinting control region important for the regulation of CDKN1C expression [4].
• In conclusion, variants in CDKN1C may contribute to the inter-individual variation in birth weight [5].

Psychiatry related information on CDKN1C

• PURPOSE: WBS is an autosomal dominant disorder that includes features such as developmental delay, cardiovascular anomalies, mental retardation and characteristic facial appearance [6].
• Monocular and binocular visual depth perception was tested in 33 patients with WBS [7].
• Patients with Williams-Beuren Syndrome (WBS, also known as Williams Syndrome) show many problems in motor activities requiring visuo-motor integration, such as walking stairs [7].
• A comparative analysis of eating and sleeping behaviours in 28 Prader-Willi- and 32 Williams-Beuren syndrome children by psychometric instruments confirms excessive food-seeking behaviours in PWS and selective food refusal in WBS as specific problems [8].

High impact information on CDKN1C

• These data support the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with the human disease Beckwith-Wiedemann syndrome (BWS) may disrupt CDKN1C expression [9].
• We and others have identified three imprinted human genes on 11p15.5, IGF2, H19, and p57KIP2, although the latter gene is separated by 700 kb from the other two, and it is unclear whether there are other imprinted genes within this large interval [10].
• p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin/Cdk complexes, and is a negative regulator of cell proliferation [11].
• An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome [11].
• The expression pattern and unique domain structure of p57 suggest that this CDI may play a specialized role in cell cycle control [12].

Chemical compound and disease context of CDKN1C

• CDKN1C expression was also decreased in many pancreatic cancer cell lines and was restored following treatment with a DNA methylation inhibitor (5-aza-2'-deoxycitidine) or, more potently, with a histone deacetylase inhibitor (trichostatin A) [4].
• However, in two genotype-quantitative trait correlation studies involving 206 glucose-tolerant offspring of type 2 diabetic patients and 359 young, healthy subjects the CDKN1C del171APVA variant associated with increased birth weight (P=0.05 and P=0.05) [5].
• The promoter of the p57 gene is, however, methylated in five of eight gastric cancer cell lines as expected from the result of the treatment with 5-aza-2'-deoxycytidine [13].
• Expression of p57KIP2 was induced in U373 and U87 malignant glioma cells with doxycycline using the tetracycline repressor system [14].
• Induction of p57 in U373 astrocytoma cells generated a small population of cells ( approximately 15%) that were nonviable, contained discrete nuclear fragments on Hoechst 33258 staining, and demonstrated ultrastructural features characteristic of apoptosis [15].

Biological context of CDKN1C

• Mutations in CDKN1C (p57(kip2)) have been identified in a small proportion of patients with BWS, and removal of the gene from mice by targeted mutagenesis produces a phenotype with elements in common with this overgrowth syndrome [16].
• Human and mouse genetic data strongly implicate another gene, CDKN1C (p57(kip2)), located in the same imprinted gene cluster on human chromosome II, in BWS. p57(KIP2) is a cyclin-dependent kinase inhibitor and is required for normal mouse embryonic development [16].
• CDKN1C expression was diminished in 10 of 17 lines and statistically correlated with the loss of methylation at DMR-LIT1 in all but three [3].
• To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines [3].
• Epigenetic down-regulation of CDKN1C/p57KIP2 in pancreatic ductal neoplasms identified by gene expression profiling [4].

Anatomical context of CDKN1C

• METHODS: The steady state levels of CDKN1C gene expression in fibroblast cells from normal individuals, and from persons with BWS who have LOM at KvDMR1, was determined by both real time quantitative polymerase chain reaction (qPCR) and ribonuclease protection assay (RPA) [17].
• In situ hybridization during mouse embryogenesis revealed that KIP2 mRNA displays a striking pattern of expression during development, showing high level expression in skeletal muscle, brain, heart, lungs, and eye [18].
• CONCLUSION: Our results suggest that damaged podocytes may inhibit p27 and p57 protein expression, but activate a cyclin D1-independent cell-cycle mechanism and mitotic cell cyclins to promote GEC proliferation in the cellular lesion of FSGS [19].
• Three of five informative patients exhibited biallelic CDKN1C expression in lymphocytes, cord blood, and kidney tissue, respectively [20].
• We conclude that the behavior of p57, but not p21, is consistent with a role as a physiological mediator of proliferative quiescence in the adrenal cortex [21].

Associations of CDKN1C with chemical compounds

• The aim of this study was to investigate if variations in the proximal promoter and the coding region of the CDKN1C and CDK4 genes are associated with type 2 diabetes or changes in related quantitative phenotypes among glucose-tolerant subjects [5].
• Retroviral-transfected, p57-expressing oral carcinoma cells showed significant resistance to green tea polyphenol-induced apoptosis [22].
• Hypermethylation of the CDKN1C promoter, a reported cause of downregulation in other cancers, was detected by bisulfite sequencing in several cell lines and appeared associated with downregulation in at least one cell line [23].
• 5. However, as the p57KIP2 gene is 500 kb centromeric to the gene encoding insulin-like growth factor 2, it is likely to be part of a large domain containing other imprinted genes [24].
• 5-aza-2'-deoxycytidine (aza-C) increases H19 expression in RD RMS cells but does not activate KIP2 expression [25].

Physical interactions of CDKN1C

• Here we demonstrate that p57 regulates actin dynamics by binding and translocating LIMK-1 from the cytoplasm into the nucleus, which in turn results in a reorganization of actin fiber [26].

Regulatory relationships of CDKN1C

• CDK4 activity is inhibited by CDKN1C, which is regulated by insulin [5].
• ZAC is an imprinted gene expressed from the paternal allele of chromosome 6q24 within a region known to harbor a tumor suppressor gene for several types of neoplasia. p57(KIP2) (CDKN1C) is a maternally expressed gene located on chromosome 11p15.5 which encodes a cyclin-dependent kinase inhibitor that may also act as a tumor suppressor gene [27].
• They also confirm other studies showing that the mechanisms associated with regulating CDKN1C expression and imprinting are separate from those regulating IGF2 imprinting [20].
• The p57 gene was activated by histone deacetylase inhibitors in all of the gastric cancer cell lines and by 5-aza-2'-deoxycytidine in five of eight gastric cell lines [13].
• 5. This loss is of maternal origin suggesting the presence of a monoallelically expressed tumor suppressor gene in this region. p57(KIP2) (KIP2) located at 11p15.5 is predominantly expressed from the maternal allele and encodes a cyclin-dependent kinase inhibitor [28].

Other interactions of CDKN1C

• Thus, control of cell cycle and suppression of cell transformation by p57 require both CDK and PCNA inhibitory activity, and disruption of either or both functions may lead to uncontrolled cell growth [29].
• We have also found two novel silencer sequences; one is located in KvDMR, a region that is thought to contain the promoter for the KCNQ1OT1 transcript, and another is in the CDKN1C gene [30].
• Mutation analyses of the two genes in 62 type 2 diabetic patients resulted in the discovery of seven variants of CDKN1C and two variants of CDK4 [5].
• OBJECTIVE: To evaluate the roles of the CDKN1C (P57KIP2) gene, which encodes for the cyclin-dependent kinase inhibitor CDNC, and the TP53 tumor suppressor gene in adrenal tumorigenesis, as a means of investigating the molecular basis of sporadic adrenal tumors, which is unknown [31].
• Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors [31].

Analytical, diagnostic and therapeutic context of CDKN1C

• In a subgroup of 48 tissues, CDKN1C expression was evaluated by RT-PCR and immunohistochemistry [31].
• In this study, we investigated the correlation between p57 expression and survival/apoptosis by Western blot analysis, caspase 3 assays and morphological analysis [22].
• Using primary human hematopoietic cells and microarray analysis, we identified p57KIP2 (p57) as the only cyclin-dependent kinase inhibitor induced by TGFbeta [32].
• By immunohistochemistry, p57KIP2 immunoreactivity was positive in 8/40 GBMs, and was primarily nuclear in location [14].
• METHODS: The CDKN1C promoter region was analysed for changes in DNA methylation using bisulphite sequencing, and for alterations in chromatin structure using the chromatin immunoprecipitation (ChIP) assay [33].

References