CDKN2A siRNA – Cyclin-Dependent Kinase Inhibitor 2a Isoform P14arf (Human)

This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

p16-INK4A iso4: a cell-cycle regulatory protein that interacts with CDK4 and CDK6, inhibiting their ability to interact with cyclins D. Inhibits the phosphorylation of the retinoblastoma protein by CDK4 or CDK6, and entry into the S phase of the cell cycle. The p16INK4A and p14ARF proteins are encoded by CDKN2A, a known tumour suppressor gene in multiple cancers. CDKN2A is inactivated in 72% of cases of lung squamous cell carcinoma: 21% by epigenetic silencing by methylation, 18% inactivating mutation, 4% by exon 1b skipping, and 29% by homozygous deletion. Defects in CDKN2A are the cause of familial atypical multiple mole melanoma-pancreatic carcinoma syndrome, Li-Fraumeni syndrome, and the melanoma-astrocytoma syndrome. The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma. Four alternatively spliced p16 isoforms have been reported. Two alternatively spliced isoforms of ARF have been reported.

Protein type: Tumor suppressor; Nucleolus; Cell cycle regulation

Chromosomal Location of Human Ortholog: 9p21

Cellular Component: nucleoplasm; nuclear body; protein complex; mitochondrion; cytoplasm; nucleolus; nucleus; cytosol

Molecular Function: cyclin-dependent protein kinase inhibitor activity; NF-kappaB binding; protein binding; DNA binding; p53 binding; ubiquitin-protein ligase inhibitor activity; protein kinase binding; transcription factor binding

Biological Process: protein polyubiquitination; positive regulation of apoptosis; positive regulation of transcription, DNA-dependent; regulation of protein stability; negative regulation of B cell proliferation; regulation of protein export from nucleus; negative regulation of cell proliferation; apoptotic mitochondrial changes; regulation of G2/M transition of mitotic cell cycle; somatic stem cell division; cell cycle arrest; caspase activation; negative regulation of immature T cell proliferation in the thymus; protein destabilization; protein stabilization; transcription, DNA-dependent; negative regulation of cyclin-dependent protein kinase activity; negative regulation of cell-matrix adhesion; positive regulation of protein sumoylation; inhibition of NF-kappaB transcription factor; Ras protein signal transduction; negative regulation of ubiquitin-protein ligase activity; negative regulation of phosphorylation; negative regulation of protein kinase activity; positive regulation of transcription from RNA polymerase II promoter; negative regulation of cell growth; mitotic cell cycle; positive regulation of DNA damage response, signal transduction by p53 class mediator; negative regulation of transcription, DNA-dependent; rRNA processing; G1/S transition of mitotic cell cycle

Disease: Melanoma-astrocytoma Syndrome; Melanoma, Cutaneous Malignant, Susceptibility To, 2; Li-fraumeni Syndrome 1; Melanoma-pancreatic Cancer Syndrome