TY - JOUR
T1 - Induction of autophagy and inhibition of tumorigenesis by beclin 1
AU - Liang, Xiao Huan
AU - Jackson, Saadiya
AU - Seaman, Matthew
AU - Brown, Kristy
AU - Kempkes, Bettina
AU - Hibshoosh, Hanina
AU - Levine, Beth
PY - 1999/12/9
Y1 - 1999/12/9
N2 - The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway, is important in normal growth control and may be defective in tumour cells. 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. 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.
AB - The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway, is important in normal growth control and may be defective in tumour cells. 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. 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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U2 - 10.1038/45257
DO - 10.1038/45257
M3 - Article
C2 - 10604474
AN - SCOPUS:0000906170
SN - 0028-0836
VL - 402
SP - 672
EP - 676
JO - Nature
JF - Nature
IS - 6762
ER -