Dysregulation of HSG Triggers Proliferative Disorders

HSG 失调会引发增殖性疾病

• 批准号: 6968763
• 负责人: Rui-Ping Xiao
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6968763
• 关键词: angiogenesis; cardiovascular disorder; cell growth regulation; cell proliferation; cytogenetics; differential display technique; fibroblast growth factor; gene expression; gene induction /repression; genetic mapping; hyperplasia; myogenesis; platelet derived growth factor; spontaneous hypertensive rat; tissue /cell culture; vascular smooth muscle

Cell hyper-proliferation has long been considered as an important etiological factor of cardiovascular diseases and cancer. Vascular proliferative disorders such as atherosclerosis and restenosis after balloon angioplasty play a central role in cardiovascular diseases, the current leading cause of death in the western countries and the predicted number one killer worldwide by 2020, but the underlying molecular mechanism is poorly understood. Using RNA differential display analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and age- and gender-matched Wistar Kyoto rats (WKY), we have identified a novel gene, named hyperplasia suppressor gene (HSG) which encodes a protein of 757 amino acids and is widely expressed in various rat tissues. We have also cloned human and mouse HSG genes, which share 95.2 and 98.4 % sequence homology, respectively, with rat HSG (rHSG). The expression of rHSG is markedly downregulated in hyperplasic SHR VSMCs relative to normal WKY VSMCs. In addition, rHSG expression is also overtly down-regulated by proliferation-stimulating factors such as platelet-derived growth factor (PDGF)?Cbasic fibroblast growth factor (bFGF), and endothelin-1 (ET-1) in cultured primary WKY VSMCs. Enforced expression of rHSG using adenoviral gene transfer markedly inhibits growth factors-mediated VSMC proliferation by inhibition of ERK1/2 MAPK activation and subsequent cell cycle arrest in G1/Go, and reduces balloon injury-induced neointimal formation by 90% in vivo, thereby preventing balloon injury-associated restenosis. In addition, HSG alos markedly inhibits proliferation and induces apoptosis in many cancer cell lines. Thus, we have identified and characterized a widely expressed and highly conserved novel gene, HSG, which exhibits an important role in regulating cell proliferation and cell death in VSMCs as well as amny other cell types. These findings not only reveal a fundamental biological function of the ubiquitously expressed and phylogenetically well-conserved gene, but also define a novel genetic pathway for cell proliferative diseases.

细胞过度增殖长期以来被认为是心血管疾病和癌症的重要病因。动脉粥样硬化和球囊血管成形术后再狭窄等血管增殖性疾病在心血管疾病中发挥着核心作用，心血管疾病是目前西方国家的主要死亡原因，预计到 2020 年将成为全球头号杀手，但其潜在的分子机制尚不清楚。通过对自发性高血压大鼠（SHR）和年龄和性别匹配的Wistar京都大鼠（WKY）培养的血管平滑肌细胞（VSMC）进行RNA差异显示分析，我们鉴定了一种新基因，称为增生抑制基因（HSG），它编码757个氨基酸的蛋白质，在多种大鼠组织中广泛表达。我们还克隆了人和小鼠 HSG 基因，它们与大鼠 HSG (rHSG) 分别具有 95.2% 和 98.4% 的序列同源性。相对于正常 WKY VSMC，增生性 SHR VSMC 中 rHSG 的表达显着下调。此外，在培养的原代WKY VSMC中，rHSG表达也被增殖刺激因子明显下调，例如血小板源性生长因子（PDGF）、C碱性成纤维细胞生长因子（bFGF）和内皮素-1（ET-1）。使用腺病毒基因转移强制表达 rHSG，通过抑制 ERK1/2 MAPK 激活和随后的 G1/Go 细胞周期停滞，显着抑制生长因子介导的 VSMC 增殖，并在体内将球囊损伤诱导的新内膜形成减少 90%，从而防止球囊损伤相关的再狭窄。此外，HSG 还显着抑制许多癌细胞系的增殖并诱导细胞凋亡。因此，我们鉴定并鉴定了一种广泛表达且高度保守的新基因 HSG，它在调节 VSMC 以及许多其他细胞类型的细胞增殖和细胞死亡中发挥着重要作用。这些发现不仅揭示了普遍表达且系统发育上高度保守的基因的基本生物学功能，而且还定义了细胞增殖性疾病的新遗传途径。