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。血管增生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，但对潜在的分子机制知之甚少。利用RNA差异显示技术，在培养的自发性高血压大鼠（SHR）和年龄和性别匹配的Wistar京都大鼠（WKY）的血管平滑肌细胞（VSMCs）中发现了一个新基因，命名为增生抑制基因（HSG）。我们还克隆了人和小鼠HSG基因，其与大鼠HSG（rHSG）分别具有95.2%和98.4%的序列同源性。与正常WKY VSMCs相比，SHR VSMCs增生时rHSG的表达明显下调。此外，rHSG的表达也明显下调增殖刺激因子，如血小板衍生生长因子（PDGF）？体外培养原代WKY大鼠VSMCs，观察bFGF、ET-1对VSMCs增殖的影响。使用腺病毒基因转移的rHSG的增强表达通过抑制ERK 1/2 MAPK活化和随后的G1/Go细胞周期停滞显著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生内膜形成减少90%，从而预防球囊损伤相关的再狭窄。此外，HSG还显著抑制许多癌细胞系的增殖并诱导凋亡。因此，我们已经确定并表征了一个广泛表达且高度保守的新基因，HSG，其在VSMCs以及其他细胞类型中调节细胞增殖和细胞死亡中发挥重要作用。这些发现不仅揭示了广泛表达的和在遗传学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.