REGULATION OF CELL PROLIFERATION

细胞增殖的调节

• 批准号: 2750472
• 负责人: MICHAEL J. GETZ
• 金额: $ 24.81万
• 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/2750472
• 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-肌动蛋白基因编码主要的结构蛋白 细胞微丝，是各种生长类别的成员 被称为细胞“即刻早期”(IE)基因的因子调节基因。 虽然这些基因的显著特征是它们的快速转录 对增殖刺激、肌肉特异性肌动蛋白的激活 基因通常只在末端分化过程中表达。 肌源性细胞系。但是，此规则的一个例外是 血管平滑肌(VSM)α-肌动蛋白基因 在平滑肌细胞分化过程中的激活，也表达了 间质中的“肌成纤维细胞”--一种与 对生长因子、细胞因子和炎症的增殖反应 刺激物。与在细胞增殖中的作用一致，申请者具有 最近发现，VSM-肌动蛋白启动子有可能被 细胞IE基因在血清刺激的成纤维细胞中的表达 文化。申请人现在提议检验细胞-- 特定类型的转录抑制机制起作用，在 部分，用于VSMα-肌动蛋白在 肌源性细胞和成纤维细胞。具体来说，申请人 假设成纤维细胞中的沉默是由于干扰 转录增强因子1(TEF-1)或密切相关的 相关蛋白协同激活VSMα-肌动蛋白 抄写。此外，申请者还提出了一种调解机制 通过最近发现的单链DNA(SsDNA)结合蛋白。 然而，在未分化的成肌细胞中，定点突变 研究清楚地表明，抑制VSMα-的机制- 肌动蛋白转录不同。