title: Dasatinib inhibits leukaemic cell survival by decreasing PRH/Hhex phosphorylation resulting in increased repression of VEGF signalling genes.
abstract: The PRH/Hhex transcription factor represses multiple genes in the VEGF signalling pathway (VSP) to inhibit myeloid cell survival. Protein kinase CK2 phosphorylates PRH and counteracts the inhibitory effect of this protein on cell survival by blocking the repression of VSP genes. Here we show that the BCR-ABL/Src kinase inhibitor dasatinib decreases PRH phosphorylation and increases PRH-dependent repression of Vegf and Vegfr-1. Moreover in the absence of PRH, dasatinib does not inhibit cell survival as effectively as in PRH expressing cells. Thus the re-establishment of gene control by PRH is in part responsible for the therapeutic effects of dasatinib.
authors.affiliation: School Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Noy
authors.forename: Kevin
authors.initials: K
authors.lastname: Gaston
authors.forename: Padma-Sheela
authors.initials: PS
authors.lastname: Jayaraman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C078492:HHEX protein, human; D018398:Homeodomain Proteins; D011743:Pyrimidines; D013844:Thiazoles; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000069439:Dasatinib