Cyclin D1 function in tumorigenesis and differentiation

描述（由申请人提供）：在不同组织学类型的上皮肿瘤中观察到细胞周期蛋白D1基因的遗传改变，从而导致编码蛋白的过表达。同样，三种C/EBP2亚型的异常表达是几种上皮癌的特征。然而，细胞周期蛋白D1和C/EBP2影响肿瘤发生的途径尚不清楚。人类肿瘤基因表达模式的生物信息学分析和直接实验表明，cyclin D1可以激活C/EBP2的转录功能。此外，cyclin D1和C/EBP2带来的转录程序可以在几种类型的人类上皮性肿瘤中看到，然而，这种转录程序与肿瘤发生之间的因果关系尚未确定。研究将涉及结构-功能分析，以了解cyclin D1如何激活C/EBP2在cyclin D1靶基因启动子处的转录功能。这些研究的目的也是为了提供试剂，如C/EBP2和cyclin D1突变体，来探讨cyclin D1与C/EBP2功能相互作用的生物学意义。为了解决细胞周期蛋白D1转录功能的生物学后果，已经开发了细胞周期蛋白D1依赖性转化试验，使用黑色素细胞和乳腺上皮细胞。利用这些系统，将从遗传学角度评估细胞周期蛋白D1的C/ ebp2依赖性转录功能对转化的贡献。第三条线索的研究灵感来自于观察到周期蛋白D1和C/EBP2是孕期乳腺发育所必需的。这一观察结果，结合上述对人类肿瘤的分析，表明cyclin D1过表达对C/EBP2转录活性的影响导致的分化受阻可能有助于肿瘤的发生。本研究将测试cyclin D1与C/EBP2之间的功能相互作用是否有助于乳腺上皮细胞分化。这将需要使用cyclin D1和C/EBP2缺陷的乳腺上皮细胞以及野生型细胞进行遗传分析。公共卫生相关性：Cyclin D1，由于其在人类上皮肿瘤（包括黑色素瘤和乳腺癌）中的基因改变，被认为是癌症的主要诱因。为了靶向细胞周期蛋白D1的治疗，有必要了解其运作的途径。针对这一需求，本研究将试图阐明cyclin D1如何影响肿瘤发生。

DESCRIPTION (provided by applicant): Genetic alterations in the cyclin D1 gene with consequent overexpression of the encoded protein are observed in epithelial tumors of diverse histological types. Similarly, aberrant expression of the three C/EBP2 isoforms characterizes several epithelial cancers. However, the pathways through which cyclin D1 and C/EBP2 operate to effect tumorigenesis are poorly understood. A combination of bioinformatic analyses of the patterns of gene expression in human cancer and direct experimentation suggests that cyclin D1 can activate the transcriptional function of C/EBP2. Further, the transcriptional program brought about by cyclin D1 and C/EBP2 can be seen in several types of human epithelial tumors-however, the causal relationship between this transcriptional program and tumorigenesis has not been established. Research to be conducted will involve structure-function analyses to understand mechanistically how cyclin D1 activates the transcriptional function of C/EBP2 at cyclin D1 target gene promoters. The intent of these studies is also to provide reagents, e.g., C/EBP2 and cyclin D1 mutants, to probe the biological significance of the functional interaction between cyclin D1 and C/EBP2. To address the biological consequences of cyclin D1's transcriptional function, cyclin D1-dependent transformation assays have been developed, using melanocytes and mammary epithelial cells. With these systems, the contribution of cyclin D1's C/EBP2-dependent transcriptional function to transformation will be assessed genetically. A third line of investigation is inspired by the observation that cyclin D1 and C/EBP2 are required for mammary gland development during pregnancy. This observation, together with the analysis of human tumors noted above, suggests that blocked differentiation resulting from the effect of overexpressed cyclin D1 on the transcriptional activity of C/EBP2 may contribute to tumorigenesis. The research will test the possibility that the functional interaction between cyclin D1 and C/EBP2 contributes to mammary epithelial cell differentiation. This will entail a genetic analysis employing cyclin D1- and C/EBP2 -deficient mammary epithelial cells, as well as wild-type cells. PUBLIC HEALTH RELEVANCE: Cyclin D1, by virtue of its genetic alterations in human epithelial tumors-including melanoma and breast cancer-is thought to contribute materially to cancer. In order to target cyclin D1 therapeutically, it is necessary to understand the pathways through which it operates. Responding to this need, the proposed research will attempt to elucidate how cyclin D1 effects tumorigenesis.