Induction of autophagy and inhibition of tumorigenesis by beclin 1
Induction of autophagy and inhibition of tumorigenesis by beclin 1
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DOI：
10.1038/45257
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发表时间：
1999-12-09
期刊：
影响因子：
64.8
通讯作者：
Levine, B
中科院分区：
文献类型：
--
作者：
Liang, XH;Jackson, S;Levine, B
自噬过程，即通过自噬体-溶酶体途径大量降解细胞蛋白的过程 (1)，对于正常生长控制很重要，但在肿瘤细胞中可能存在缺陷 (2)。然而，人们对哺乳动物细胞中自噬的遗传介质或其在肿瘤发展中的作用知之甚少。编码 Beclin 1（参考文献 3）的哺乳动物基因是一种新型 Bcl-2 相互作用的卷曲螺旋蛋白，与酵母自噬基因 apg6/vps30（参考文献 4、5）具有结构相似性，并且在 40-75% 的散发性人类乳腺癌和卵巢癌中被单等位基因缺失 (6)。在这里，我们使用基因转移技术证明，beclin 1 通过靶向破坏 agp6/vps30 来促进自噬缺陷型酵母和人 MCF7 乳腺癌细胞中的自噬。 beclin 1 在 MCF7 细胞中的自噬促进活性与抑制 MCF7 细胞增殖、体外克隆形成和裸鼠肿瘤发生有关。此外，内源性 Beclin 1 蛋白在人乳腺上皮癌细胞系和组织中表达通常较低，但在正常乳腺上皮细胞中普遍高水平表达。因此，beclin 1是一种哺乳动物自噬基因，可以抑制肿瘤发生，并且在人乳腺癌中表达水平降低。这些发现表明，自噬蛋白表达的减少可能有助于乳腺癌和其他人类恶性肿瘤的发生或进展。
The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway(1), is important in normal growth control and may be defective in tumour cells(2) However, little is known about the genetic mediators of autophagy in mammalian cells or their role in tumour development. The mammalian gene encoding Beclin 1 (ref. 3), a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30 (refs 4, 5), and is mono-allelically deleted in 40-75% of sporadic human breast cancers and ovarian cancers(6). Here we show using gene-transfer techniques, that beclin 1 promotes autophagy in autophagy-defective yeast with a targeted disruption of agp6/vps30, and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of beclin 1 in MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogenous Beclin 1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissue, but is expressed ubiquitously at high levels in normal breast epithelia. Thus, beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of breast and other human malignancies.