INK4 GENE FAMILY IN NEOPLASIA

肿瘤中的 INK4 基因家族

• 批准号: 6318302
• 负责人: MARTINE F. ROUSSEL (SHERR)
• 金额: $ 19.77万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6318302
• 关键词: cell cycle; cyclin dependent kinase; cyclins; fluorescent in situ hybridization; gene expression; gene mutation; gene targeting; genetic promoter element; genetically modified animals; human genetic material tag; human tissue; laboratory mouse; molecular cloning; molecular oncology; neoplasm /cancer genetics; pediatric neoplasm /cancer; tissue /cell culture; tumor suppressor genes

D-type cyclins (D1, D2, and D3) assemble with cyclin-dependent kinases (CDK4 and CDK6) to yield holoenzymes that govern the rate of progression through the first gap phase (G1) of the cell division cycle. Active cyclin D-CDK complexes phosphorylate the retinoblastoma protein (pRb) in mid to late G1 phase, thereby releasing pRb-bound transcription factors such as E2F whose trans-activating functions are necessary for the entry of cells into S phase. Whereas the induction and assembly of catalytically active cyclin D-CDK4 (and -CDK6) complexes is positively regulated by mitogens, a novel family of polypeptide inhibitors of CDK4 - the so-called Ink4 proteins - can block cyclin D-CDK assembly and activation to prevent G1 exit. Therefore, Ink4 proteins potentially act at the "top" of the following growth regulatory pathway: Ink4 Proteins - Cyclin D-CDK4 (or CDK6) -> pRb - E2F -> S Phase Entry The central goal of this proposal is to determine whether different INK4 genes act as tumor suppressors and whether their disruption etiologically contributes to human cancer. Genes encoding two Ink4 proteins, P16INK4a and P15INK4b, are tandemly linked on human chromosome 9p21, and INK4a(MTS1) sustains deletions and inactivating mutations in numerous forms of human cancer. Disruption of P16INK4a and pRb function in tumors is mutually exclusive, supporting the idea that both act in a common pathway. However, complications in determining the general role of INK4a in tumor suppression include its close linkage to INK4b(MTS2) and, surprisingly, the ability of INK4a to encode a second, unrelated protein (P19ARF, derived from an alternative reading frame) that can also halt the cell cycle. Furthermore, genes on human chromosomes 1p and 19p also encode Ink4 proteins, p18INK4c and p19INK4d, which appear to be biochemically indistinguishable from p16INK4a in their ability to inhibit cyclin D-CDK activity and to induce pRb-dependent G1 phase arrest. We therefore hope to address the following questions: (1) Why are there four INK4 genes, and what is the basis of their biological specificity? (2) Is P16INK4a the only bona fide tumor suppressor, or do inactivation of p19ARF and other INK4 genes also contribute to tumor formation.

d型细胞周期蛋白（D1， D2和D3）与细胞周期蛋白依赖性激酶组装