Cyclin D1 function in tumorigenesis and differentiation

项目总结/摘要 观察到细胞周期蛋白D1基因的遗传改变，随之而来的是编码蛋白的过表达 在不同组织学类型的上皮肿瘤中。同样，三种C/EBP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/EBP的作用途径 对肿瘤发生的影响知之甚少。基因模式的生物信息学分析组合 细胞周期蛋白D1在人类癌症中的表达和直接实验表明， C/EBP的功能。此外，可以看到由细胞周期蛋白D1和C/EBP引起的转录程序 在几种类型的人类上皮肿瘤-然而，这种转录之间的因果关系， 程序和肿瘤发生尚未建立。研究将涉及结构-功能 分析以了解细胞周期蛋白D1如何在细胞周期蛋白D1上激活C/EBP的转录功能 D1靶基因启动子。这些研究的目的还在于提供试剂，例如，C/EBP和细胞周期蛋白D1 突变体，探讨细胞周期蛋白D1和C/EBP之间的功能相互作用的生物学意义。到 解决细胞周期蛋白D1的转录功能的生物学后果，细胞周期蛋白D1依赖 已经开发了使用黑素细胞和乳腺上皮细胞的转化测定法。与这些 系统中，细胞周期蛋白D1的C/EBP依赖性转录功能对转化的贡献将是 基因评估第三条研究路线的灵感来自于细胞周期蛋白D1和C/EBP的观察， 在怀孕期间乳腺发育所需的。这一观察，以及对 上述的人肿瘤，表明由过表达的 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 cyclin D1和C/EBP之间的功能性相互作用可能有助于乳腺上皮细胞 分化这将需要使用细胞周期蛋白D1和C/EBP缺陷的乳腺癌进行遗传分析。 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.