PRH/Hhex controls cell survival through coordinate transcriptional regulation of vascular endothelial growth factor signaling.
The proline-rich homeodomain protein (PRH) plays multiple roles in the control of gene expression during embryonic development and in the adult. Vascular endothelial growth factor (VEGF) is a mitogen that stimulates cell proliferation and survival via cell surface receptors including VEGFR-1 and VEGFR-2. VEGF signaling is of critical importance in angiogenesis and hematopoiesis and is elevated in many tumors. Here we show that PRH binds directly to the promoter regions of the Vegf, Vegfr-1, and Vegfr-2 genes and that in each case PRH represses transcription. We demonstrate that overexpression or knockdown of PRH directly impinges on the survival of both leukemic and tumor cells and that the modulation of VEGF and VEGF receptor signaling by PRH mediates these effects. Our findings demonstrate that PRH is a key regulator of the VEGF signaling pathway and describe a mechanism whereby PRH plays an important role in tumorigenesis and leukemogenesis.
Noy
Peter
P
Institute for Biomedical Research, Birmingham University Medical School, Edgbaston, Birmingham B15 2TT, United Kingdom.
Williams
Hannah
H
Sawasdichai
Anyaporn
A
Gaston
Kevin
K
Jayaraman
Padma-Sheela
PS
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D056970:Co-Repressor Proteins; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D056970:Co-Repressor Proteins; D004273:DNA, Neoplasm; C078492:HHEX protein, human; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C434946:Tle1 protein, mouse; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2