Abstract
The proline rich homeodomain protein (PRH), also known as haematopoietically expressed homeobox (HHEX), is an essential transcription factor in embryonic development and in the adult. The PRH protein forms oligomeric complexes that bind to tandemly repeated PRH recognition sequences within or at a distance from PRH-target genes and recruit a variety of PRH-interacting proteins. PRH can also bind to other transcription factors and co-regulate specific target genes either directly through DNA binding, or indirectly through effects on the activity of its partner proteins. In addition, like some other homeodomain proteins, PRH can regulate the translation of specific mRNAs. Altered PRH expression and altered PRH intracellular localisation, are associated with breast cancer, liver cancer and thyroid cancer and some subtypes of leukaemia. This is consistent with the involvement of multiple PRH-interacting proteins, including the oncoprotein c-Myc, translation initiation factor 4E (eIF4E), and the promyelocytic leukaemia protein (PML), in the control of cell proliferation and cell survival. Similarly, multiple PRH target genes, including the genes encoding vascular endothelial growth factor (VEGF), VEGF receptors, Endoglin, and Goosecoid, are known to be important in the control of cell proliferation and cell survival and/or the regulation of cell migration and invasion. In this review, we summarise the evidence that implicates PRH in tumourigenesis and we review the data that suggests PRH levels could be useful in cancer prognosis and in the choice of treatment options.
Highlights
The proline rich homeodomain protein/haematopoietically expressed homeobox (PRH/HHEX), is a transcription factor encoded by the HHEX gene [1,2,3]
PRH can phenocopy the Lmo2 oncoprotein in inducing self-renewal when overexpressed in mice and elevated PRH causes a T-cell leukemia, which is strikingly similar to that caused by Lmo2. These results suggested that PRH is an important mediator of Lmo2-driven T-cell self-renewal and leukemia [41, 67, 71]
Altered PRH levels and altered PRH subcellular localisation are associated with several cancers and with some subtypes of leukaemia
Summary
The proline rich homeodomain protein/haematopoietically expressed homeobox (PRH/HHEX), is a transcription factor encoded by the HHEX gene [1,2,3]. Several regulatory elements—either intronic or situated in the 5′ flanking region of the Prh/HHEX gene—have been identified, as well as putative or experimentally established regulatory proteins and signalling pathways One such regulator is the Sp family of transcription factors: in MH1C1 rat hepatoma and K562 human erythroleukemia cells, Sp1 and Sp3 bind GC-rich regions within the 5′ flanking region of the Prh/HHEX gene and activate transcription [31]. The PRH N-terminal repression domain binds to the β subunit of CK2 and CK2 phosphorylates two residues (S163 and S177) within the PRH homeodomain [54] Phosphorylation at these sites inhibits PRH DNA-binding in vitro and in cells, and blocks the transcriptional regulation of PRH target genes [54, 55]. Incubation of K562 cells with the translation inhibitor anisomycin indicated that hypo-phosphorylated PRH is longer lived
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