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 （CDK4 和 CDK6）产生控制进展速度的全酶 穿过细胞分裂周期的第一个间隙期 (G1)。 积极的 细胞周期蛋白 D-CDK 复合物磷酸化视网膜母细胞瘤蛋白 (pRb) G1期中后期，从而释放pRb结合的转录因子 例如E2F，其进入需要反式激活功能 细胞进入S期。 而感应和组装 催化活性细胞周期蛋白 D-CDK4（和 -CDK6）复合物呈阳性 受有丝分裂原调节，这是一种新型的 CDK4 多肽抑制剂家族 - 所谓的 Ink4 蛋白 - 可以阻断细胞周期蛋白 D-CDK 的组装 激活以防止 G1 退出。 因此，Ink4 蛋白可能发挥作用 在以下生长调节途径的“顶部”： Ink4 蛋白 - 细胞周期蛋白 D-CDK4（或 CDK6） -> pRb - E2F -> S 期进入 该提案的中心目标是确定不同的INK4是否 基因作为肿瘤抑制因子，以及它们的破坏是否与病因有关 导致人类癌症。 编码两种 Ink4 蛋白 P16INK4a 的基因 和 P15INK4b，串联连接在人类染色体 9p21 上，并且 INK4a(MTS1) 在许多细胞中维持缺失和失活突变 人类癌症的形式。 肿瘤中 P16INK4a 和 pRb 功能的破坏 是相互排斥的，支持两者以共同的方式行事的想法 途径。 然而，确定 INK4a 的一般作用的复杂性 在肿瘤抑制中的作用包括其与 INK4b(MTS2) 的密切联系， 令人惊讶的是，INK4a 能够编码第二种不相关的蛋白质 （P19ARF，源自替代阅读框架）也可以停止 细胞周期。 此外，人类染色体1p和19p上的基因也 编码 Ink4 蛋白 p18INK4c 和 p19INK4d，它们似乎是 其抑制能力在生化上与 p16INK4a 没有区别 细胞周期蛋白 D-CDK 活性并诱导 pRb 依赖性 G1 期停滞。 我们 因此希望解决以下问题：（1）为什么有四个 INK4基因，其生物学特异性的基础是什么？ (2) P16INK4a 是唯一真正的肿瘤抑制因子吗？ p19ARF 和其他 INK4 基因也有助于肿瘤的形成。