Dysregulation of HSG Triggers Proliferative Disorders

细胞过度增殖一直被认为是心血管疾病和癌症的重要病因。血管增殖性疾病，如动脉粥样硬化和球囊血管成形术后再狭窄，在心血管疾病中起着核心作用，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、性别匹配的Wistar Kyoto大鼠（WKY）培养血管平滑肌细胞（VSMCs）的RNA差异显示分析，我们发现了一个名为增生抑制基因（HSG）的新基因，该基因编码757个氨基酸的蛋白，在大鼠各种组织中广泛表达。我们还克隆了人和小鼠HSG基因，与大鼠HSG （rHSG）的序列同源性分别为95.2%和98.4%。与正常WKY VSMCs相比，增生性SHR VSMCs中rHSG的表达明显下调。此外，rHSG的表达也被增殖刺激因子如血小板衍生生长因子（PDGF）明显下调。培养的原代WKY VSMCs中碱性成纤维细胞生长因子（bFGF）和内皮素-1 （ET-1）的表达。通过腺病毒基因转移强化表达rHSG，通过抑制ERK1/2 MAPK激活和随后的G1/Go细胞周期阻滞，显著抑制生长因子介导的VSMC增殖，并在体内减少90%球囊损伤诱导的新内膜形成，从而防止球囊损伤相关的再狭窄。此外，HSG还能显著抑制多种癌细胞的增殖和诱导凋亡。因此，我们已经鉴定并表征了一个广泛表达和高度保守的新基因HSG，它在VSMCs以及许多其他细胞类型的细胞增殖和细胞死亡调节中发挥重要作用。这些发现不仅揭示了这个普遍表达且在系统发育上保守的基因的基本生物学功能，而且为细胞增殖性疾病确定了新的遗传途径。

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.