Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. Academic Article uri icon

Overview

MeSH

  • Animals
  • Autophagy
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Western
  • Cell Movement
  • Cell Proliferation
  • Endothelial Cells
  • Erythropoietin
  • Heterozygote
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lung
  • Melanoma
  • Mice
  • Neoplasm Transplantation
  • Protein Stability
  • RNA, Small Interfering
  • Stress, Physiological

MeSH Major

  • Anoxia
  • Apoptosis Regulatory Proteins
  • Neovascularization, Pathologic

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.

publication date

  • August 2011

has subject area

  • Animals
  • Anoxia
  • Apoptosis Regulatory Proteins
  • Autophagy
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Western
  • Cell Movement
  • Cell Proliferation
  • Endothelial Cells
  • Erythropoietin
  • Heterozygote
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lung
  • Melanoma
  • Mice
  • Neoplasm Transplantation
  • Neovascularization, Pathologic
  • Protein Stability
  • RNA, Small Interfering
  • Stress, Physiological

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3149693

PubMed ID

  • 21685724

Additional Document Info

start page

  • 829

end page

  • 839

volume

  • 7

number

  • 8