title: RTEF-1, an upstream gene of hypoxia-inducible factor-1α, accelerates recovery from ischemia.
abstract: The amount of available hypoxia-inducible factor (HIF)-1α has been considered to be largely a consequence of post-translational modification by multiple ubiquitin-proteasome pathways. However, the role of transcriptional regulation of HIF-1α is less certain, and the mechanisms of transcriptional regulation of HIF-1α require further investigation. Here we report that related transcriptional enhancer factor-1 (RTEF-1), a member of the TEF transcriptional factor family, transcriptionally regulates the HIF-1α gene under normoxic and hypoxic conditions. The expression of HIF-1α mRNA was decreased in endothelial cells in which RTEF-1 was knocked down with siRNA. Sequential deletional analysis of the HIF-1α promoter revealed that the MCAT-like element in the HIF-1α promoter was essential for HIF-1α transcription. Binding of RTEF-1 to the MCAT-like element was confirmed by ChIP. Treatment of endothelial cells with a HIF-1 inhibitor resulted in retardation of RTEF-1-induced proliferation and tube formation. Moreover, increased HIF-1α expression was observed in transgenic mice expressing RTEF-1 under the VE-cadherin promoter (VE-Cad/RTEF-1). VE-Cad/RTEF-1 mice subjected to hindlimb ischemia demonstrated increased levels of HIF-1α, accelerated recovery of blood flow, and increased capillary density compared with littermate controls. These results identify RTEF-1 as a regulator of HIF-1α transcription, which results in up-regulation of HIF-1α and acceleration of recovery from ischemia.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Jiaping
authors.initials: J
authors.lastname: Wu
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Song
authors.forename: Qinhui
authors.initials: Q
authors.lastname: Song
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Cully
authors.forename: Angela
authors.initials: A
authors.lastname: Messmer-Blust
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Shi-Yin
authors.initials: SY
authors.lastname: Foo
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D001483:Base Sequence; D001775:Blood Circulation / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009124:Muscle Proteins; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors