Cyclin D1 function in tumorigenesis and differentiation

项目摘要/摘要 观察到细胞周期蛋白D1基因的遗传改变导致编码蛋白的过度表达 在不同组织类型的上皮性肿瘤中。同样，三种C/EBP异构体的异常表达 是几种上皮性癌症的特征。然而，细胞周期蛋白D1和C/EBP？的作用途径 对肿瘤发生的影响还知之甚少。基因模式的生物信息学分析的组合 在人类肿瘤中的表达和直接实验表明，细胞周期蛋白D1可以激活转录 C/EBP的功能。此外，还可以看到Cyclin D1和C/EBP带来的转录程序 然而，在几种类型的人类上皮性肿瘤中，这种转录之间的因果关系 计划和肿瘤发生尚未确定。将进行的研究将涉及结构功能 从机制上理解细胞周期蛋白D1如何激活C/EBP的转录功能 D1靶基因启动子。这些研究的目的也是为了提供试剂，例如C/EBP和细胞周期蛋白D1 探讨细胞周期蛋白D1与C/EBP功能相互作用的生物学意义。至 阐述细胞周期蛋白D_1‘S转录功能的生物学后果，细胞周期蛋白D_1依赖 利用黑素细胞和乳腺上皮细胞，已经开发出转化试验。有了这些 系统中，细胞周期蛋白D1‘S C/EBP依赖的转录功能对转化的贡献将是 从基因上评估的。第三条线的研究灵感来自观察到细胞周期蛋白D1和C/EBP是 孕期乳腺发育所必需的。这一观察结果，连同对 上面提到的人类肿瘤，表明分化受阻是由于过度表达的影响 Cyclin D1对C/EBP？转录活性的影响可能与肿瘤的发生有关。这项研究将测试 细胞周期蛋白D1与C/EBP？功能相互作用参与乳腺上皮细胞分化的可能性 差异化。这将需要使用细胞周期蛋白D1和C/EBP缺陷的乳腺进行遗传分析 上皮细胞，以及野生型细胞。

Project Summary / Abstract 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/EBP¿ isoforms characterizes several epithelial cancers. However, the pathways through which cyclin D1 and C/EBP¿ 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/EBP¿. Further, the transcriptional program brought about by cyclin D1 and C/EBP¿ 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/EBP¿ at cyclin D1 target gene promoters. The intent of these studies is also to provide reagents, e.g., C/EBP¿ and cyclin D1 mutants, to probe the biological significance of the functional interaction between cyclin D1 and C/EBP¿. 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/EBP¿-dependent transcriptional function to transformation will be assessed genetically. A third line of investigation is inspired by the observation that cyclin D1 and C/EBP¿ 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/EBP¿ may contribute to tumorigenesis. The research will test the possibility that the functional interaction between cyclin D1 and C/EBP¿ contributes to mammary epithelial cell differentiation. This will entail a genetic analysis employing cyclin D1- and C/EBP¿ -deficient mammary epithelial cells, as well as wild-type cells.