INK4 GENE FAMILY IN NEOPLASIA

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CDK 6）产生控制进展速率的全酶 通过细胞分裂周期的第一间隙期（G1）。 活性 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中期至晚期，从而释放pRb结合的转录因子 例如E2 F，其反式激活功能对于进入是必需的 细胞进入S期。 而归纳和组装 具有催化活性的细胞周期蛋白D-CDK 4（和-CDK 6）复合物是阳性的， 调节有丝分裂原，一个新的家庭的多肽抑制剂的CDK 4- 所谓的Ink 4蛋白-可以阻断细胞周期蛋白D-CDK组装， 阻止G1退出。 因此，Ink 4蛋白可能起作用， 位于以下生长调节途径的“顶端”： Ink 4蛋白-细胞周期蛋白D-CDK 4（或CDK 6）-> pRb-E2 F-> S期进入 本提案的中心目标是确定不同的INK 4 基因作为肿瘤抑制因子， 会导致人类癌症 编码两种Ink 4蛋白P16 INK 4a的基因 和P15 INK 4 b串联连接在人染色体9 p21上，并且 INK 4a（MTS 1）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P16 INK 4a和pRb功能的破坏 是相互排斥的，支持两者共同作用的观点， 通路 然而，确定INK 4a的一般作用的并发症 在肿瘤抑制中包括其与INK 4 b（MTS 2）紧密联系， 令人惊讶的是，INK 4a编码第二种不相关蛋白质的能力 （P19 ARF，来自另一个阅读帧），也可以停止 细胞周期 此外，人类染色体1 p和19 p上的基因也 编码Ink 4蛋白，p18 INK 4c和p19 INK 4d，它们似乎是 在生物化学上与p16 INK 4a无法区分， 细胞周期蛋白D-CDK活性和诱导pRb依赖性G1期阻滞。 我们 因此，希望解决以下问题：（1）为什么有四个 INK 4基因，其生物学特异性的基础是什么？（二） P16 INK 4a是唯一真正的肿瘤抑制因子，还是使其失活？ p19 ARF和其他INK 4基因也有助于肿瘤形成。

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.