REGULATION OF CELL PROLIFERATION

细胞增殖的调节

• 批准号: 2232604
• 负责人: MICHAEL J. GETZ
• 金额: $ 24.47万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2232604
• 关键词: DNA binding protein; animal tissue; cell cycle; chromatography; fibroblasts; gene expression; gene induction /repression; gene mutation; genetic enhancer element; genetic promoter element; nucleic acid structure; site directed mutagenesis; transcription factor; vascular smooth muscle

DESCRIPTION (adapted from the applicant's abstract): The cytoskeletal beta- and gamma-actin genes encode the principal structural proteins of cellular microfilaments and are members of a diverse class of growth factor-regulated genes termed cellular "immediate early" (IE) genes. While the salient feature of these genes is their rapid transcriptional activation in response to proliferation stimuli, muscle-specific actin genes are generally expressed only during terminal differentiation of cells of myogenic lineage. An exception to this rule, however, is the vascular smooth muscle (VSM) alpha-actin gene which, in addition to activation during smooth muscle cell differentiation, is also expressed in stromal "myofibroblasts"-specialized cell types associated with proliferative responses to growth factors, cytokines, and inflammatory stimuli. Consistent with a role in cell proliferation, the applicant has recently shown that the VSM-actin promoter has the potential to be expressed as a cellular IE gene in serum-stimulated fibroblasts in culture. The applicant now proposes to test the hypothesis that cell- type-specific transcriptional repression mechanisms are responsible, in part, for the differential patterns of VSM alpha-actin expression in myogenic cells and in fibroblasts. Specifically, the applicant postulates that silencing in fibroblasts results from interference with the ability of transcriptional enhancer factor 1 (TEF-1), or a closely related protein, to synergistically activate VSM alpha-actin transcription. Moreover, the applicant proposes a mechanism mediated by recently identified single-stranded DNA (ssDNA) binding proteins. In undifferentiated myoblasts, however, site- directed mutagenesis studies clearly indicate that the mechanisms which repress VSM alpha- actin transcription differ.

描述（改编自申请人的摘要）：细胞骨架 β-和γ-肌动蛋白基因编码的主要结构蛋白， 细胞微丝和成员的不同类的增长 因子调节的基因称为细胞“立即早期”（IE）基因。 虽然这些基因的显著特征是它们的快速转录， 对增殖刺激的反应，肌肉特异性肌动蛋白 基因通常只在细胞的终末分化过程中表达， 肌原细胞谱系。然而，这一规则的一个例外是， 血管平滑肌（VSM）α-肌动蛋白基因，除了 在平滑肌细胞分化过程中激活，也表达 在基质“肌成纤维细胞”-与 对生长因子、细胞因子和炎症的增殖反应 刺激。与细胞增殖中的作用一致，申请人具有 最近表明，VSM-肌动蛋白启动子有可能被 在血清刺激的成纤维细胞中表达为细胞IE基因， 文化申请人现在提出测试细胞- 类型特异性转录抑制机制负责， 部分，对于VSM α-肌动蛋白表达的差异模式， 生肌细胞和成纤维细胞。具体而言，申请人 假设成纤维细胞中的沉默是由干扰 转录增强因子1（TEF-1）的能力，或一个密切相关的 相关蛋白，协同激活VSM α-肌动蛋白 转录。此外，申请人提出了一种机制， 最近发现的单链DNA（ssDNA）结合蛋白。 然而，在未分化的成肌细胞中， 研究清楚地表明，抑制VSM α- 肌动蛋白转录不同。