Disease relevance of CDKN2C

• Structural analysis of the CDKN2A, CDKN2B, and CDKN2C genes in hepatoblastoma cases showed the absence of deletions and/or point mutations [1].
• Taken together, our results indicate that CDKN2C is rarely altered in meningiomas [2].
• Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study [3].
• Moreover, alteration of CDKN2C does not appear to be involved in the genesis of rhabdomyosarcoma [4].
• Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis [5].

High impact information on CDKN2C

• Methylation of INK4C (CDKN2C) was observed in four of 23 human MBs, and p18(INK4C) protein expression was extinguished in 14 of 73 cases [6].
• Ectopic expression of p18 or p16 suppresses cell growth with a correlated dependence on endogenous wild-type pRb [7].
• Thus, CDK inhibitors, in particular p18, are likely to play a pivotal role in controlling cell cycle arrest and cell death in terminal differentiation of late-stage B cells to plasma cells via inhibition of pRb phosphorylation by CDK6 [8].
• Overexpression of p18 in IgM-bearing lymphoblastoid cells, which differentiated in response to IL-6 but did not exit the cell cycle, reconstituted coupled differentiation and cell cycle arrest [8].
• Compared with their corresponding single mutant littermates, the p18(-)(/)(-); Men1(+/)(-) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas [9].

Chemical compound and disease context of CDKN2C

• We have identified an alanine to proline substitution at codon 72 of the p18 gene in BT-20 human breast cancer cells [10].

Biological context of CDKN2C

• One atypical meningioma with loss of heterozygosity on 1p carried a somatic CDKN2C mutation (c.202C>T: R68X) [2].
• Neither homozygous deletions nor intragenic mutations of the p18 and p19 genes were found except in an ovarian cancer cell line, SKOV3, harboring a single base pair deletion in exon 1 of p19 [11].
• Homozygous deletions of the CDKN2C/p18INK4C gene on the short arm of chromosome 1 in anaplastic oligodendrogliomas [12].
• Because the CDKN2C gene, which encodes the homologous p18INK4C cell cycle regulatory protein, maps to chromosomal band 1p32, CDKN2C is an attractive candidate for the oligodendroglioma suppressor gene on chromosome 1 [12].
• Our data thus provide evidence for more than a single oligodendroglioma-associated tumor suppressor gene on 1p and implicate CDKN2C as a candidate tumor suppressor gene altered in a low fraction of oligodendroglial tumors [13].

Anatomical context of CDKN2C

• Finally, the sequence analysis of genomic DNA isolated from T cell lymphocytes of healthy individuals exhibited that the codon reported as last of exon 2 of the CDKN2C gene is rather the first codon of exon 3 [14].
• p16INK4A, p15INK4B, and p18 proteins are highly specific inhibitors of cyclin-dependent serine/threonine kinase (CDK) activities required for GI-S transition in the eukaryotic cell division cycle [4].
• Loss of both p18 and p27 function resulted in the spontaneous development by 3 months of age of at least eight different types of hyperplastic tissues and/or tumors in the pituitary, adrenals, thyroid, parathyroid, testes, pancreas, duodenum, and stomach [15].
• NH2-terminal sequencing indicates that p18 is distinct from other nuclear envelope components, but has similarity to the mitochondrial isoquinoline-binding protein [16].
• We show here that p18 is an integral membrane protein specific to the erythrocyte nuclear envelope which binds to LBR and B-type lamins [16].

Associations of CDKN2C with chemical compounds

• Taken together, these data suggest a critical role of p18 Bax in gefitinib-induced apoptosis [17].
• Gefitinib did not affect the amount of total and phosphorylated p53 at serine 15, but upregulated the expression of total Bax, with subsequent increase in p18 Bax, an active form of Bax [17].
• Furthermore, cycloheximide inhibition experiments reveal that the fraction of p18 that resides in the outer nuclear membrane does not represent nascent chains en route to the inner nuclear membrane, but rather material in equilibrium with the p18 that partitions with the inner nuclear membrane [16].
• Western blot analysis of 2-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels confirmed its identity as lamin B. Phosphorylation of p17 and p18 decreased following 1,25-(OH)2D3 treatment [18].
• Inhibition by genistein indicated that p18 mRNA expression was dependent on cellular tyrosine kinases in these cells [19].

Physical interactions of CDKN2C

• Gel shift analyses using p18 promoter-derived probes led to the identification of several multiprotein complexes that were found to contain different combinations of E2F proteins and/or Sp1 [20].
• This mutation abrogates the ability of p18 to interact with CDK6 and renders p18 deficient in suppressing cell growth in a colony formation assay [10].
• The paradigm of p18 suggests that transmembrane complexes formed by the nuclear lamins and LBR provide potential docking sites for integral membrane proteins of the nuclear envelope that equilibrate between the rough endoplasmic reticulum and the inner nuclear membrane [16].

Enzymatic interactions of CDKN2C

• In all cell lines exposed to As(2)O(3), p21 Bax was proteolytically cleaved in a calpain-dependent way into the more proapoptotic p18 Bax, which was detected exclusively in a mitochondria-enriched subcellular fraction [21].

Regulatory relationships of CDKN2C

• We and others found that overexpressed E2F proteins up-regulate p18 expression [20].

Other interactions of CDKN2C

• Here we analyze the imprinting status of three additional CKIs, the abnormal expression and/or chromosomal localization of which has been implicated in human malignancy: CDKN1A, CDKN1B, and CDKN2C [22].
• Indeed, p16INK4A and p15INK4B (products of expression of CDKN2A and CDKN2B respectively) were not observable while pl8INK4C (which is codified by CDKN2C) was clearly detectable in the samples analyzed [1].
• We report the first detailed structure-function analyses of p18INK4C (p18), which is a homologue of the important tumor suppressor p16INK4A (p16) [23].
• The present investigation reports the results of screening the 100 Swedish melanoma families for germline mutations in the CDK4, CDKN2C and TP53 genes [3].
• Mutational inactivation of these elements revealed that the Sp1 sites were important for the basal activity of the promoter but could also mediate the effects of E2F1 on the p18 promoter [20].

Analytical, diagnostic and therapeutic context of CDKN2C

• Using Western blot analysis, subsets of 26 human cancer cell lines were examined for p18 expression and 39 cell lines for p19 expression [11].
• Chromatin immunoprecipitation experiments demonstrated that E2F1 and E2F4 associate with the p18 promoter in unperturbed cells [20].
• In order to assess p18 growth-suppressor gene alterations in hematological neoplasms, we investigated 31 lymphoma and leukemia cell lines by PCR for both exons of this gene [24].
• The expression levels of CDKN2C, CRADD, and IGFBP-2 genes were significantly associated with the event-free survival of the patients in AML [25].
• We separated p17 and p18 by SDS-PAGE and obtained N-terminal amino acid sequence to identify these phosphorproteins as histones H2b and H3, respectively [18].

References