Yue Zhenyu, Jin Shengkan, Yang Chingwen, Levine Arnold J, Heintz Nathaniel
Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82. doi: 10.1073/pnas.2436255100. Epub 2003 Dec 1.
The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
贝林1的生化特性表明其在两个至关重要的细胞生物学途径中发挥作用：自噬和凋亡。我们在此表明，贝林1基因敲除（beclin 1-/-）的突变小鼠在胚胎发育早期死亡，而贝林1基因杂合缺失（beclin 1+/-）的突变小鼠患有高发性自发肿瘤。这些肿瘤持续表达野生型贝林1的mRNA和蛋白质，证实贝林1是一个单倍剂量不足的肿瘤抑制基因。贝林1基因敲除的胚胎干细胞具有严重改变的自噬反应，而它们对血清撤除或紫外线照射的凋亡反应正常。这些结果表明贝林1是哺乳动物自噬的关键组成部分，并确立了自噬在肿瘤抑制中的作用。它们都为最近将贝林-1与人类癌症相关联的证据提供了生物学解释，并表明在该途径中起作用的其他基因的突变可能通过自噬失调导致肿瘤形成。
