Anti-CDKN1C monoclonal antibody, clone 633DU0.6.2

Human chromosomal region 11p15.5, which is homologous to mouse chromosome region 7F5, is a well-known imprinted region. The CDKN1C/KCNQ1OT1 imprinted domain, which is one of two imprinted domains at 11p 15.5, includes nine imprinted genes regulated by an imprinting center (IC). The CDKN1C/KCNQ1OT1 IC is a differentially methylated region of KCNQIOTI (KCNQ1OT-DMR) with DNA methylation on the maternal allele and no methylation on the paternal allele. CDKN1C (alias p57(KIP2)), an imprinted gene with maternal expression, encoding a cyclin-dependent kinase inhibitor, is a critical gene within the,CDKN1C/KCNQ1OT1 domain. In Beckwith-Wiedemann syndrome (BWS), approximately 50% of patients show loss of DNA methylation accompanied by loss of histone H3 Lys9 dimethylation on maternal KCNQ1OT-DMR, namely an imprinting. disruption, leading to diminished expression of CDKN1C. In cancer, at least three molecular mechanisms imprinting disruption, aberrant DNA methylations at the CDKN1C promoter, and loss of heterozygosity (LOH) of the maternal allele - are seen and all three result in diminished expression of CDKN1C. Imprinting disruption of the CDKN1C/KCNQ1OT1 domain is involved in the development of both BWS and cancer and it changes the maternal epigenotype to the paternal type, leading to diminished CDKN1C expression. In this review, we describe recent advances in epigenetic control of the CDKN1C/KCNQ1OT1 imprinted domain in both humans and mice.

Atherosclerosis is characterized by excessive proliferation of neointimal leukocytes and vascular smooth muscle cells (VSMCs). In mice, the manipulation of cell cycle inhibitors such as CDKN1B (p27) and CDKN1A (p21) modifies the risk of developing atherosclerosis. In humans, CDKN1A, CDKN1B and CDKN1C (p57) are differentially expressed in normal versus atherosclerotic vessels. A DNA-polymorphism within the CDKN1B promoter has been associated with myocardial infarction (MI). In the present study, we analyzed the effect of CDKN1A, CDKN1C and CDKN2A (p16) polymorphisms on MI-risk. A total of 316 patients (all male, < 55 years) and 434 controls were genotyped, and the allele and genotype frequencies were compared between the two groups. Two CDKN1C polymorphisms, a promoter GT-repeat and a variable number of repeats of the amino acid PAPA-motif, were associated with MI. The presence of two alleles <= 11-repeats (9/11, 10/11 and 11/11 genotypes) was significantly less frequent among patients (p < 0.001). This difference was also significant when analyzing the subpopulation of smokers (p = 0.004), suggesting a protective role for these low-repeat genotypes (OR = 0.49, 95% CI = 0.32-0.73). The PAPA-BB homozygotes were significantly less frequent in patients, but this could be attributed to a linkage disequilibrium between the 11-repeats and B alleles. No significantly different frequencies between patients and controls for the four CDKN1A (-1026A/G, -754G/C, -369G/C and Ser31Arg) and the three CDKN2A (-523G/A, +22G/A and Ala148Thr) polymorphisms was found. In conclusion, we provide here genetic evidence for the association between DNA-variants in the CDKN1C/p57 gene and the risk of atherosclerosis and MI.