Noy, Peter John (2011)
Ph.D. thesis, University of Birmingham.
| AbstractPRH is a transcriptional repressor that regulates development of the haematopoietic and vascular systems. VEGF is a mitogen that stimulates cell survival via cell surface receptors including VEGFR1 and VEGFR2. This thesis identifies Vegf, Vegfr1, and Vegfr2 as bona fide PRH target genes and shows PRH can control cell survival through the modulation of VEGF and VEGF receptor signalling. CK2 is a stress-activated protein kinase with pleiotropic activity and CK2 phosphorylation of PRH inhibits its DNA binding activity. Here I show that CK2 can antagonise PRH induced cell death and transcriptional regulation. Furthermore I show that CK2 reduces PRH stability and decreases nuclear retention of PRH. The oncogenic BCR-ABL fusion protein increases CK2 activity. I show that Inhibition of BCR-ABL in CML cells results in decreased PRH phosphorylation and the down-regulation of PRH target genes. Reestablishment of gene control by PRH is partly responsible for the therapeutic effects of BCR-ABL inhibition in CML and that the reestablishment of PRH function could be valuable for the treatment of leukaemias with elevated CK2 activity. These data show that PRH is a key regulator of the VEGF family and loss of PRH transcriptional activity, through elevated CK2, has a role in leukaemogenesis.
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