title: Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis.
abstract: Beclin 1, a tumor suppressor protein, acts as an initiator of autophagy in mammals. Heterozygous disruption of Beclin 1 accelerates tumor growth, but the underlying mechanisms remain unclear. We examined the role of Beclin 1 in tumor proliferation and angiogenesis, using a primary mouse melanoma tumor model. Beclin 1 (Becn1 (+/-) ) hemizygous mice displayed an aggressive tumor growth phenotype with increased angiogenesis under hypoxia, associated with enhanced levels of circulating erythropoietin but not vascular endothelial growth factor, relative to wild-type mice. Using in vivo and ex vivo assays, we demonstrated increased angiogenic activity in Becn1 (+/-) mice relative to wild-type mice. Endothelial cells from Becn1 (+/-) mice displayed increased proliferation, migration and tube formation in response to hypoxia relative to wild-type cells. Moreover, Becn1 (+/-) cells subjected to hypoxia displayed increased hypoxia-inducible factor-2α (HIF-2α) expression relative to HIF-1α. Genetic interference of HIF-2α but not HIF-1α, dramatically reduced hypoxia-inducible proliferation, migration and tube formation in Becn1 (+/-) endothelial cells. We demonstrated that mice deficient in the autophagic protein Beclin 1 display a pro-angiogenic phenotype associated with the upregulation of HIF-2α and increased erythropoietin production. These results suggest a relationship between Beclin 1 and the regulation of angiogenesis, with implications in tumor growth and development.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hong-Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000378:metabolism*; D001343:Autophagy; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D000071186:Beclin-1; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000096:biosynthesis; D006579:Heterozygote; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000648:ultrastructure; D008545:Melanoma / Q000098:blood supply / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000378:metabolism; D013312:Stress, Physiological; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D000071186:Beclin-1; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C115010:Becn1 protein, mouse