P53 AND CDK4 FUNCTION IN THE TGF BETA PATHWAY

转化生长因子β（TGF-β）是一种旁分泌多肽， 在调节细胞生长中起着关键作用，但其确切的机制是， 行动是不完全理解的。 细胞周期蛋白依赖性激酶4（CDK 4）是 被认为在GI期进展中发挥重要作用 细胞周期。 cdk 4合成的下调在 在TGF-b-G1生长停滞机制中的作用。 对TGF-β的抵抗是一种 肿瘤表型 建议的工作旨在获得更好的机械理解 TGF-β是如何导致胃肠道细胞周期停滞的， 这也适用于细胞周期调控的其他设置。 这项工作将 试图确定TGF-β如何阻止cdk 4蛋白的合成。 它会问是否有TGF-β诱导的蛋白质， CDK 4 mRNA的5 ′非翻译区，并阻止其 翻译. 肿瘤抑制因子p53似乎参与了 TGF-β通路。突变型p53通过阻止TGF-β的表达而赋予TGF-β抗性。 响应细胞因子下调CDK 4。 野生型但不是 突变型p53可以抑制CDK 4信息的翻译。 这项工作将 试图阐明p53如何影响CDK 4的翻译。 放松管制 cdk 4合成显著降低了pS3蛋白的野生型水平 在肺上皮细胞中。 拟议的工作旨在确定如何 这发生了。 辐射诱导细胞周期阻滞的机制是 不清楚 然而，已知p53在此过程中起重要作用。 过程 这项工作将试图问一些电路是否 在TGF-b通路中起作用也在生长停滞机制中起作用 由辐射引起的。 对TGF-β的抗性见于许多人类癌症。 此外，这种表型可以在体外选择。 使用 在研究TGF-β通路中获得的机制信息 将确定如何抵抗TGF-β发生时，它是 选择为。 这项工作的最终目标是获得一个 了解G1细胞周期蛋白依赖性激酶及其调节 伴侣（细胞周期蛋白）在促进G1期进展和退出中的作用以及肿瘤如何 抑制因子，如p53，调节通过G1的进展。

Transforming growth factor beta (TGF-b), a paracrine polypeptide, plays a critical role in regulating cell growth, but its precise mechanism of action is not completely understood. Cyclin dependent kinase 4 (cdk4) is thought to play an important role in the progression through the GI phase of the cell cycle. Downregulation of cdk4 synthesis plays a significant role in the TGF-b-G1 growth arrest mechanism. Resistance to TGF-b is a neoplastic phenotype. The proposed work is aimed at obtaining a better mechanistic understanding of how TGF-b causes a GI cell cycle arrest and whether the principles involved apply to other settings of cell cycle regulation. The work will attempt to determine the how TGF-b prevents the synthesis of cdk4 protein. It will ask if there are proteins induced by TGF-b which specifically bind to the 5 prime untranslated region of CDK4 mRNA and prevent its translation. The tumor suppressor, p53, appears to be involved in the TGF-b pathway. Mutant p53 confers resistance to TGF-b by preventing the downregulation of cdk4 in response to the cytokine. Wild type but not mutant p53 can inhibit the translation of the CDK4 message. The work will attempt to elucidate how p53 affects the translation of CDK4. Deregulated cdk4 synthesis significantly reduces the wild type levels of pS3 protein in lung epithelial cells. The proposed work is aimed at determining how this occurs. The mechanism of radiation induced cell cycle arrest is unclear. However, it is known that p53 plays a significant role in this process. The work will attempt to ask whether some of the circuits operating in the TGF-b pathway also operate in the growth arrest mechanism caused by irradiation. Resistance to TGF-b is seen in many human cancers. Furthermore, this phenotype can be selected for in vitro. Using the mechanistic information gained in studying the TGF-b pathway an effort will be made to determine how resistance to TGF-b occurs when it is selected for. The ultimate goal of this work is aimed at obtaining an understanding of the role G1 cyclin dependent kinases and their regulatory partners (cyclins) play in promoting G1 progression and exit and how tumor suppressors, such as p53, regulate the progression through G1.