Disease relevance of Cdkn2c

• Using a P1-phage genomic clone of INK4d for fluorescence in situ hybridization analysis, the location of this gene was mapped to chromosome 19p13 [1].
• Loss of p18, like that of p27, but not other CDK inhibitor genes, leads to a gradual progression from intermediate lobe pituitary hyperplasia in young mice to an adenoma by 10 months of age with a nearly complete penetrance [2].
• Mice lacking both p18 and p27, like mice chimeric for Rb deficiency, invariably died from pituitary adenomas by 3 months [2].
• We used a tissue-microarray approach to analyze p18INK4c expression in 316 Hodgkin lymphomas (HLs) [3].
• Hypermethylation of the p18INK4c promoter was detected in 2 of 4 HL-derived cell lines, but in none of 7 non-Hodgkin lymphoma (NHL)-derived cell lines [3].

High impact information on Cdkn2c

• Low p18 expression was frequently observed in different human cancer cell lines and tissues [4].
• Here we describe the mouse p18 loss-of-function phenotype and a role for p18 in the DNA damage response [4].
• Inactivation of both p18 alleles caused embryonic lethality, while heterozygous mice showed high susceptibility to spontaneous tumors. p18 was induced and translocated to the nucleus in response to DNA damage [4].
• T and B lymphocytes develop normally in p18-deficient mice, but both exhibit increased cellularity and a higher proliferative rate upon mitogenic stimulation [2].
• Chromatin immunoprecipitation studies reveal that menin directly associates with regions of the p27 and p18 promoters and increases methylation of lysine 4 (Lys-4) in histone H3 associated with these promoters [5].

Chemical compound and disease context of Cdkn2c

• To develop a model of anterior pituitary proliferation to study the pathogenesis of pituitary tumors, we crossed the glycoprotein hormone alpha-subunit (alphaSU)-null mice that develop thyroid-stimulating hormone (TSH) cell hyperplasia with p18-null mice [6].

Biological context of Cdkn2c

• Additionally, RET2A-dependent p18 repression is required and sufficient to increase cell proliferation [7].
• Distinctly, there is a remarkable induction of p18INK4c mRNA and protein that was not seen in the closely related nondifferentiating 3T3-C2 cell line, suggesting that p18 induction in 3T3-L1 cells is related to cell differentiation, not cell cycle arrest [8].
• In the neocortex, p18INK4c was expressed precisely at those developmental stages when neuroblasts switch from a symmetric to an asymmetric pattern of cell division with concomitant increases in their G1 interval [9].
• The abundance of INK4d mRNA oscillates in a cell-cycle-dependent manner with expression lowest at mid G1 and maximal during S phase [1].
• Whereas p18INK4c and p19INK4d may regulate pre- and postnatal development, p16INK4a more likely plays a checkpoint function during cell senescence that underscores its selective role as a tumor suppressor [10].

Anatomical context of Cdkn2c

• The INK4d gene is ubiquitously expressed as a single 1.4-kb mRNA with the highest levels detected in thymus, spleen, peripheral blood leukocytes, fetal liver, brain, and testes [1].
• In situ hybridization of mouse embryo sections demonstrated expression of mRNAs encoding two polypeptide inhibitors (p18INK4c and p19INK4d) of cyclin D-dependent kinase (CDK) 4 and CDK6 in the central nervous system [9].
• Marked INK4d expression was seen in dorsal root ganglia, spinal cord, and focally throughout the brain, but primarily in postmitotic neurons [9].
• Neural expression of INK4d continued postnatally into adulthood in postmitotic cells of the dentate gyrus, the pyramidal layer of the hippocampus, and in discrete regions of the cerebral cortex, cerebellum, thalamus, and brainstem [9].
• p18INK4c and p27KIP1 are required for cell cycle arrest of differentiated myotubes [11].

Associations of Cdkn2c with chemical compounds

• To investigate the cause of p18INK4c repression in RS cells, the methylation status of the p18INK4c promoter was analyzed by methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing [3].
• In contrast, in p18/p27 knockout animals, the G1 phase was unchanged, but the amount of proliferating hepatocytes (5-bromo-2'-deoxyuridine [BrdU] and PCNA positive) 48 hours after PH was elevated [12].
• One of the major Trichostatin A (TSA)-responsive elements is a specific Sp1 binding site in the INK4d promoter [13].
• We provide evidence that the cyclin-dependent kinase inhibitors p18 and p27 may be part of the timer and that thyroid hormone may help developing cardiac myocytes stably withdraw from the cell cycle [14].
• The predicted amino acid sequence of As-p18 exhibits similarities to the intracellular lipid-binding protein (iLBP) family including retinoid- and fatty acid-binding proteins (FABP) [15].

Other interactions of Cdkn2c

• The p19INK4d and p18INK4c proteins formed complexes with either CDK4 or CDK6 in a temporal pattern consistent with the results of in situ hybridization [9].
• Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1 [16].

Analytical, diagnostic and therapeutic context of Cdkn2c

• Reconstituted mice with p18-deficient HSCs under the condition of repetitive proliferative stress (serial transplantation) were followed for >3 years [17].
• Surprisingly, however, Northern blot analysis yields mRNA for As-p18 not only in the early larval stages, but also the unembryonated egg, third-stage larvae, and ovaries of adult worms, even though the protein is not detectable from any of those sources [15].

References