Disease relevance of Cdkn2b

• The p15INK4b promoter region was hypermethylated in two additional 2',3'-dideoxycytidine-induced lymphomas [1].
• Deletion of p16INK4a and/or p15INK4b was seen in 8 of 10 cell lines derived from spindle carcinomas, the most advanced stage of skin carcinogenesis [2].
• We examined 99 lung adenocarcinomas of C3H/HeJ x A/J F1(C3AF1) and A/J x C3H/HeJ F1(AC3F1) mouse hybrids and 18 (13 metastatic, 5 nonmetastatic) tumorigenic mouse lung epithelial cell lines for p15INK4b and p16INK4a gene inactivation [3].
• This was discovered using a cell line which constitutively expresses c-myc from a retrovirus vector and which was reported to have undergone deletion of genes encoding the Ink 4 tumor suppressors p15 and p16 [4].
• Moreover, the overall incidence and latency of fibrosarcomas were substantially increased and shortened, respectively, in a p15INK4b-defective background [5].

High impact information on Cdkn2b

• We now report on a gene on human chromosome 11, at the junction of the T-cell tumour-associated chromosomal translocation t(11; 14) (p15; q11) and known as the 11p15 gene or Ttg, which is believed to be involved in the pathogenesis of the tumour [6].
• However, the two anti-DNA antibodies were found to immunoprecipitate viral proteins from retrovirus-infected cells. mAb 512 reacted with gp70, both in cell membrane lysates and in purified form; mAb 319 reacted with gp85, which contains both gp70 and the retroviral protein p15 [7].
• Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15INK4b messenger RNA in primary cells and are, as a consequence, deficient in immortalization [8].
• Why downregulation of c-myc expression by TGFbeta is required for rapid activation of p15INK4b has remained unknown [9].
• While heterologous antisera to purified gp71 and p15 of MuLV reacted to a certain degree with rhabdomyosarcoma virus 114 and rat leukemia virus, natural mouse antibody did not [10].

Chemical compound and disease context of Cdkn2b

• The p16INK4a (alpha and beta form) and p15INK4b genes were analysed for homozygous deletion, hypermethylation and point mutation in B6C3F1 mouse lymphomas induced by 2',3'-dideoxycytidine or 1,3-butadiene [1].
• Five viral proteins--matrix (MA, p15), capsid (CA, p30), nucleocapsid (NC, p10), integrase (IN), and the envelope glycoprotein (SU, gp70)--were located by immunolabeling using gold probes [11].

Biological context of Cdkn2b

• In addition, the comparison suggests that a gene conversion event is part of the evolution of the human p15 and p16 genes [12].
• However, de novo methylation of the 5' CpG islands of the murine p15INK4b and p16INK4a genes was found to be highly frequent [13].
• The genes of murine cyclin D-dependent kinase inhibitors, p15INK4b and p16INK4a, are located in a region of chromosome 4 where overlapping deletions were found in lung adenocarcinomas [3].
• INK4c and INK4d are expressed during mouse embryogenesis in stereotypic tissue-specific patterns and are also detected, together with INK4b, in tissues of young mice [14].
• These findings provide new insights into the tumorigenic role of Rgr as a potent oncogene and show that p15INK4b can act as a tumor suppressor gene [5].

Anatomical context of Cdkn2b

• Expression of p16INK4a and p15INK4b was induced when mouse embryos were disrupted and cultured as mouse embryo 'fibroblasts' (MEFs) [15].
• In apparent contrast, comparison of two clonally related squamous and spindle cell lines derived from a single carcinoma showed unusually high levels of p16INK4a and p15INK4b only in the invasive spindle cells [2].
• A wide panel of murine induced T-cell lymphomas have been analysed for p16INK4a or p15INK4b alterations [13].
• Whereas an immortal mouse lung epithelial cell line (E10) and two metastatic tumor cell lines (LM1 and E9) expressed p16INK4a-beta and p15INK4b mRNA, the alpha transcript of p16INK4a was detected in only the LM1 cell line [3].
• Although methylation of the p15INK4b 3'-UTR is low in normal thymus, increased levels (up to 100%) of specific methylation in this region are found in up to 30% of radiation- or carcinogen-induced thymic lymphomas, correlating with decreased gene expression [16].

Associations of Cdkn2b with chemical compounds

• In contrast, homozygous deletions spanning the p16INK4a and p15INK4b loci were observed in only two of 31 1,3-butadiene-induced tumours [1].
• Like the insulin-activated autophosphorylation of the receptor's beta subunit (on tyrosine), activation of phosphorylation of p15 is specific, with insulin-like growth factors 1 and 2, epidermal growth factor, and platelet-derived growth factor being inactive [17].
• The temporal kinetic relationship of insulin-activated receptor beta-subunit phosphorylation, followed by the phosphorylation of p15 and then increased hexose uptake rate, is consistent with an intermediary signaling role for pp15 in insulin-stimulated glucose uptake [17].
• An in-frame stop codon within the new exon, called exon 1beta, leads to translation of a Mr 10,000 protein identical to the NH2 terminus of p15 but contains a novel, basic COOH terminus [18].
• Similarly, interferon did not affect labeling or chasing of precursor protein carrying the p15 determinants; labeling of p15 itself could not be studied because it does not contain methionine [19].

Physical interactions of Cdkn2b

• Using a mouse macrophage cell line (Bac1.2F5), we found that most of Cdk4 bound to p15 when cells were in a quiescent state [20].

Regulatory relationships of Cdkn2b

• Although Cdkn2b (p15(INK4b)) mRNA was expressed in the Myc tumors, many transcripts were aberrant in size and contained only exon 1 [21].
• Thus, allelic loss and promoter hypermethylation of the p15INK4b gene is particular to radiation-induced lymphoid leukaemias and is independent of p16INK4a and p19ARF gene promoter/exon 1 hypermethylation [22].

Other interactions of Cdkn2b

• The Ink4b gene (Cdkn2b) encodes p15(Ink4b), a cyclin-dependent kinase inhibitor [23].
• The activities of these kinases are negatively regulated by a number of proteins, such as p15INK4b, p21WAF1/Cip1, and p27Kip1, that physically associate with cyclins, cyclin-dependent kinases (Cdk), or cyclin-Cdk complexes [24].
• The significant decrease in p15 expression in tumors provides additional evidence that TGF-beta signaling may be markedly attenuated during colon tumorigenesis [25].
• On chromosome 4, at least three distinct regions of allelic deletions could be identified: one proximal to 22 cM; the second close to the p16INK4a/p15INK4b locus, which is commonly deleted in various tumors; and the third one in the proximity of Mom1 [26].
• This was not the case for p15(INK4b) or calretinin (Cdkn2b and Calb2, respectively) [27].

Analytical, diagnostic and therapeutic context of Cdkn2b

• We studied bone marrow samples of 42 newly diagnosed and untreated patients with acute lymphoblastic leukemia for the incidence of deletions of p16INK4a/p14ARF and p15INK4b using Southern blot analysis and determined the clinical outcome with regard to complete remission (CR) duration, event-free survival, and overall survival [28].
• Southern blot analysis revealed homozygous deletions of the p16INK4a gene locus in three of the nine lines, along with the genes encoding p15INK4b and p19ARF [29].
• This protein was shown by immunoprecipitation to have antigenic determinants of MuLV p30, p15, and p10, but not gp70, suggesting that p(75) represents a polyprotein composed of virion core components [30].
• Expression and analysis of p15 and epitope-tagged p10 in cells by immunohistochemistry showed similar localization of both to the cytoplasm and nucleus in mink epithelial cells and cytoplasmic localization in mouse fibroblasts [18].
• When analyzed by two-dimensional diagonal gels (nonreducing/reducing), only the I-E bands are revealed by autoradiography, indicating that the putative p15 that associates with I-E may not be accessible to surface labeling [31].

References