Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function

Beclin 1 encodes a Bcl-2-interacting coiled-coil protein with autophagy and tumor suppressor function and is monoallelically deleted in 40-75% of spor adic human breast and ovarian cancers. Beclin 1 contains a leucine-rich nuc lear export signal motif raising the possibility that its autophagy and/or tumor suppressor function may require regulated, CRM1-dependent, nucleocyto plasmic transport. In this study, we show that wild-type Beclin 1 colocaliz es with both intracytoplasmic organelles and nuclei in COS7 monkey kidney a nd 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 Be clin 1, the nuclear export mutant of Beclin 1 fails to promote nutrient dep rivation-induced autophagy and fails to inhibit irt vitro clonigenicity and in vivo tumorigenicity of MCF7 cells. Thus, beclin 1 has a leptomycin B-se nsitive leucine-rich nuclear export signal that is required for its autopha gy and tumor suppressor function. These findings suggest that the CRM1 nucl ear export pathway may be important in the functional regulation of autopha gic growth control.