Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor

Proceedings of the National Academy of Sciences of the United States of America - Tập 100 Số 25 - Trang 15077-15082 - 2003
Zhenyu Yue1, Shengkan Jin1, Chingwen Yang1, Arnold J. Levine1, Nathaniel Heintz1
1Laboratory of Molecular Biology, Howard Hughes Medical Institute, and Gene Targeting Facility, The Rockefeller University, 1230 York Avenue, New York, NY 10021; Department of Pharmacology, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854; and Pediatrics Department, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08903

Tóm tắt

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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 100 Số 25

15077-15082

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