title: Protein kinase CK2 inactivates PRH/Hhex using multiple mechanisms to de-repress VEGF-signalling genes and promote cell survival.
abstract: Protein kinase CK2 promotes cell survival and the activity of this kinase is elevated in several cancers including chronic myeloid leukaemia. We have shown previously that phosphorylation of the Proline-Rich Homeodomain protein (PRH/Hhex) by CK2 inhibits the DNA-binding activity of this transcription factor. Furthermore, PRH represses the transcription of multiple genes encoding components of the VEGF-signalling pathway and thereby influences cell survival. Here we show that the inhibitory effects of PRH on cell proliferation are abrogated by CK2 and that CK2 inhibits the binding of PRH at the Vegfr-1 promoter. Phosphorylation of PRH by CK2 also decreases the nuclear association of PRH and induces its cleavage by the proteasome. Moreover, cleavage of phosphorylated PRH produces a stable truncated cleavage product which we have termed PRHΔC (HhexΔC). PRHΔC acts as a transdominant negative regulator of full-length PRH by sequestering TLE proteins that function as PRH co-repressors. We show that this novel regulatory mechanism results in the alleviation of PRH-mediated repression of Vegfr-1. We suggest that the re-establishment of PRH function through inhibition of CK2 could be of value in treatment of myeloid leukaemias, as well as other tumour types in which PRH is inactivated by phosphorylation.
authors: Division of Immunity and Infection, School of Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Peter
authors: P
authors: Noy
authors: Anyaporn
authors: A
authors: Sawasdichai
authors: Padma-Sheela
authors: PS
authors: Jayaraman
authors: Kevin
authors: K
authors: Gaston
mesh_terms: D047390:Casein Kinase II / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D012097:Repressor Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: C078492:HHEX protein, human; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D047390:Casein Kinase II