Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2

Abstract

Transcriptional activity of p53, a central regulatory switch in a network controlling cell proliferation and apoptosis, is modulated by protein stability and post-translational modifications including phosphorylation and acetylation. Here we demonstrate that the human serine/threonine kinase homeodomain-interacting protein kinase-2 (HIPK2) colocalizes and interacts with p53 and CREB-binding protein (CBP) within promyelocytic leukaemia (PML) nuclear bodies. HIPK2 is activated by ultraviolet (UV) radiation and selectively phosphorylates p53 at Ser 46, thus facilitating the CBP-mediated acetylation of p53 at Lys 382, and promoting p53-dependent gene expression. Accordingly, the kinase function of HIPK2 mediates the increased expression of p53 target genes, which results in growth arrest and the enhancement of UV-induced apoptosis. Interference with HIPK2 expression by antisense oligonucleotides impairs UV-induced apoptosis. Our results imply that HIPK2 is a novel regulator of p53 effector functions involved in cell growth, proliferation and apoptosis.

Body language: the function of PML nuclear bodies in apoptosis regulation

“…22,23 Upon high-dose UV-radiation, HIPK2 localises together with p53 and CBP in PML-NBs and phosphorylates p53 at serine 46. 24,25 HIPK2 expression results in p53-dependent apoptosis that is associated both with p53 Ser46 phosphorylation and Lys382 acetylation, 24,25 modifications previously shown to trigger p53 activation and apoptosis. [139][140][141][142] A recent publication suggests that the nucleoplasmic fraction of PML IV mediates the effect on p53 Ser46 phosphorylation and Lys382 acetylation during premature senescence, indicating that the PML-p53 interaction can also take place in the nucleoplasm.…”

“…89 HIPKs belong to the dual-specificity tyrosine phosphorylation-regulated kinase family of protein kinases 90 and function in transcriptional regulation, 91,92 growth suppression 93 and apoptosis. 24,25 HIPK2, which mediates p53 phosphorylation and ultraviolet (UV)-induced apoptosis 24,25 (for details, see section on 'Regulation of p53 activity in PML-NBs') was found to interact with TRADD when overexpressed in 293T cells. 94 Whether this interaction is of importance for the TRADD-or TRADD-DD-induced cell killing remains to be determined in the future.…”

“…Although the molecular function of PMLNBs is currently not clear, there is accumulating evidence that PML-NBs are regulatory domains involved in various biological processes, including protein degradation, 5 transcriptional regulation, 8,9 cell growth, 10,11 antiviral response, 12,13 cellular senescence, [14][15][16][17] tumour suppression, 18 DNA repair 19,20 and apoptosis. [21][22][23][24][25] However, how can one explain that so many different and unrelated processes are linked to these nuclear domains? Since PML-NBs contain several dozens of functionally different residents (Figure 1), the current model is that PML-NBs play an important role in the regulation of these processes by controlling the function of its residents by altering their post-translational modification pattern and regulating their subcellular distribution.…”

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

“…HIPK2 was identified by a yeast two-hybrid system as a p53-interacting protein (D 'Orazi et al, 2002;Hofmann et al, 2002). HIPK2 binds to the C-terminal domain of p53 and specifically phosphorylates p53 at the NH 2 -terminal Ser46 for the p53-mediated transcriptional activation of proapoptotic factors such as p53AIP1, PIG3, Bax, Noxa, Puma and KILLER/DR5 (D 'Orazi et al, 2002;Di Stefano et al, 2004a;Pistritto et al, 2007), as well as for the repression of the antiapoptotic factor galectin-3 (Cecchinelli et al, 2006).…”

“…HIPK2 can be activated by several types of stress, including ultraviolet, ionizing radiation and drugs, such as cisplatin (CDDP), adriamycin (ADR) and roscovitin (D 'Orazi et al, 2002;Hofmann et al, 2002;Di Stefano et al, 2004a;Dauth et al, 2007;Wesierska-Gadek et al, 2007). On the other hand, few studies report that HIPK2 is inactivated in tumors by some mechanisms including hypoxia-driven proteasomal degradation that consequently also affect p53's function leading to chemoresistance and tumor progression (see below).…”