Induction of autophagy and inhibition of tumorigenesis by beclin 1.
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, a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30, 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.
Liang
X H
XH
Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York 10032, USA.
Jackson
S
S
Seaman
M
M
Brown
K
K
Kempkes
B
B
Hibshoosh
H
H
Levine
B
B
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D005656:Fungal Proteins / Q000235:genetics; D018014:Gene Transfer Techniques; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D014407:Tumor Cells, Cultured; D033921:Vesicular Transport Proteins
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D005656:Fungal Proteins; D008565:Membrane Proteins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; C402377:VPS30 protein, S cerevisiae; D033921:Vesicular Transport Proteins