HESR1/CHF2 suppresses VEGFR2 transcription independent of binding to E-boxes.
The bHLH transcription factor HESR1 (CHF2) acts downstream of notch to regulate cardiovascular development and angiogenesis, at least in part through down-regulation of the VEGF receptor, VEGFR2. Surprisingly, we find that HESR1 interacts with the promoter in endothelial cells (EC) not through direct binding to the E-boxes, but through intermediary interactions with GC-box-binding proteins. The bHLH and orange domains of HESR1 are sufficient for repression in EC, likely through recruitment of co-repressors, however, the C-terminal YRPW motif is not required. The VEGFR2 promoter contains a functional initiator element but no TATA box, however, addition of a TATA sequence renders the promoter resistant to inhibition by HESR1. In agreement with this finding, the NrCAM, TK, and CMV promoters, which have TATA boxes, cannot be repressed. Thus, HESR1 represses VEGFR2 through interactions with SP-1-like factors and requires an Inr element in the absence of a TATA box. Our findings illuminate an important mechanism for notch/HESR1 regulation of VEGF-induced angiogenesis.
Holderfield
Matthew T
MT
Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
Henderson Anderson
April M
AM
Kokubo
Hiroki
H
Chin
Michael T
MT
Johnson
Randy L
RL
Hughes
Christopher C W
CC
D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; C405694:Hairy, HRT1 protein