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Author(s): Liang XH; Jackson S; Seaman M; Brown K; Kempkes B; Hibshoosh H; Levine B
Title: Induction of autophagy and inhibition of tumorigenesis by beclin 1
Source: NATURE 402 (6762): 672-676
Date: 1999 DEC 9
Document Type: Journal : Article
DOI:
Language: English
Comment:
Address: Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA.
Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. Addenbrookes Hosp, Cambridge Inst Med Res, Dept Clin Biochem, Cambridge CB2 2XY, England. GSF, Natl Res Ctr Environm & Hlth, Inst Clin Mol Biol, D-81377 Munich, Germany. Reprint: Levine, B, Columbia Univ Coll Phys & Surg, Dept Med, 630 W 168th St,
New York, NY 10032 USA. E-mail:
Author Keywords:
KeyWords Plus: ISOLATED RAT HEPATOCYTES; PROTEIN-DEGRADATION; SACCHAROMYCES-
CEREVISIAE; CELLS; MECHANISMS; BRCA1; YEAST; FIBROBLASTS; VACUOLE
Abstract: 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.
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