title: Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function.
abstract: Beclin 1 encodes a Bcl-2-interacting coiled-coil protein with autophagy and tumor suppressor function and is monoallelically deleted in 40-75% of sporadic human breast and ovarian cancers. Beclin 1 contains a leucine-rich nuclear export signal motif raising the possibility that its autophagy and/or tumor suppressor function may require regulated, CRM1-dependent, nucleocytoplasmic transport. In this study, we show that wild-type Beclin 1 colocalizes with both intracytoplasmic organelles and nuclei in COS7 monkey kidney and MCF7 human breast carcinoma cells. Inhibition of CRM1-dependent nuclear export with leptomycin B or mutation of the nuclear export signal motif of Beclin 1 results in predominantly nuclear localization. Unlike wild-type Beclin 1, the nuclear export mutant of Beclin 1 fails to promote nutrient deprivation-induced autophagy and fails to inhibit in vitro clonigenicity and in vivo tumorigenicity of MCF7 cells. Thus, beclin 1 has a leptomycin B-sensitive leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function. These findings suggest that the CRM1 nuclear export pathway may be important in the functional regulation of autophagic growth control.
authors: Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA.
authors: X H
authors: XH
authors: Liang
authors: J
authors: J
authors: Yu
authors: K
authors: K
authors: Brown
authors: B
authors: B
authors: Levine
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D019556:COS Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016384:Consensus Sequence; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D016147:Genes, Tumor Suppressor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007930:Leucine / Q000235:genetics; D008565:Membrane Proteins; D009154:Mutation / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D005231:Fatty Acids, Unsaturated; D008565:Membrane Proteins; D011506:Proteins; D007930:Leucine; C038753:leptomycin B