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Protein kinase CK2 inactivates PRH/Hhex using multiple mechanisms to de-repress VEGF-signalling genes and promote cell survival

Noy, Peter; Sawasdichai, Anya; Jayaraman, Padma-Sheela; Gaston, Kevin

Authors

Peter Noy

Anya Sawasdichai

Padma-Sheela Jayaraman



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 PRH?C (Hhex?C). PRH?C 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.

Citation

Noy, P., Sawasdichai, A., Jayaraman, P., & Gaston, K. (2012). Protein kinase CK2 inactivates PRH/Hhex using multiple mechanisms to de-repress VEGF-signalling genes and promote cell survival. Nucleic Acids Research, 40(18), 9008--9020. https://doi.org/10.1093/nar/gks687

Journal Article Type Article
Acceptance Date Jun 21, 2012
Online Publication Date Jul 26, 2012
Publication Date Oct 1, 2012
Deposit Date Oct 31, 2018
Publicly Available Date Mar 29, 2024
Journal Nucleic Acids Research
Print ISSN 0305-1048
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 40
Issue 18
Pages 9008--9020
DOI https://doi.org/10.1093/nar/gks687
Public URL https://nottingham-repository.worktribe.com/output/1037608
Publisher URL https://academic.oup.com/nar/article/40/18/9008/2411925

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