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的蛋白激酶结合 (CDK4和CDK6)产生控制进展速度的全酶 通过细胞分裂周期的第一个间隙阶段(G1)。主动型 细胞周期蛋白D-CDK复合体磷酸化视网膜母细胞瘤蛋白 G1期中后期，从而释放pRb结合的转录因子 例如E2F，其反式激活功能对于进入是必需的 细胞进入S时相。鉴于细胞的诱导和组装 催化活性的细胞周期蛋白D-CDK4(和-CDK6)络合物是正性的 有丝分裂原调控下的CDK4多肽抑制剂家族-- 所谓的INK4蛋白-可以阻止细胞周期蛋白D-CDK的组装和 激活以防止G1退出。因此，INK4蛋白具有潜在的作用 处于以下增长调控途径的“顶端”： INK4蛋白-Cyclin D-CDK4(或CDK6)-&gt；pRb-E2F-&gt；S相 这项提议的中心目标是确定不同的INK4 基因作为肿瘤抑制因子以及它们的破坏是否是病因 会导致人类癌症。编码两种INK4蛋白的基因p16INK4a 和p15INK4b，紧密连锁在人类染色体9p21上，并且 Ink4a(MTS1)在许多基因中维持缺失和失活突变 各种形式的人类癌症。肿瘤中p16INK4a和pRb功能的紊乱 是相互排斥的，支持两者都在共同行动的想法 路径。然而，确定INK4a的一般作用的复杂情况 在肿瘤抑制方面包括其与INK4b(MTS2)的紧密连锁， 令人惊讶的是，INK4a编码第二个无关蛋白质的能力 (P19ARF，从替代阅读框派生)，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，似乎是 在生物化学上与p16INK4a的抑制能力没有区别 细胞周期蛋白D-CDK活性，并诱导pRb依赖的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，还是失活的 P19ARF和其他INK4基因也与肿瘤的形成有关。