The finding of p53 misfolding upon HIPK2 depletion was corroborated by in vivo studies in mice with the transgenic MMTV-neu spontaneous breast cancer model that revealed low HIPK2 gene expression in the tumor tissue compared to normal tissue, that correlated with misfolded p53 ��-Nicotinamide mw [29]. Zinc treatment in combination with anticancer drug adryamicin remarkably reduced spontaneous tumor growth compared to drug treatment alone, restoring wild-type p53 (wtp53) conformation and p53 apoptotic transcriptional activity [29]. Among the regulators of the HIPK2-p53 signaling axis in response to DNA damage is the LIM (Lin-11. Isl-I and Mec3) domain protein Zyxin, a

regulator of the actin skeleton and focal adhesions, that stabilizes HIPK2 by inhibiting Siah-1-mediated HIPK2 degradation [30]. Depletion of Zyxin, therefore, inhibits HIPK2 stabilization and DNA damage-induced p53Ser46 phosphorylation and apoptosis. Another molecule that fine-tunes the p53 activation threshold in response to differing severities of genotoxic stress

is Axin that allows distinct complexes formation of p53 with molecules Pirh2, Tip60 and HIPK2 [31]. Under sublethal DNA damage, Pirh2 PF-01367338 order abrogates Axin-induced p53Ser46 phosphorylation by competing with HIPK2 for binding to Axin. Under lethal DNA damage Tip abrogates Pirh2-Axin binding forming an Axin-Tip60-HIPK2-p53 NCT-501 supplier complex that allows p53 apoptotic activation [31]. HIPK2 regulates molecules involved in p53-dependent and -independent apoptosis in response to genotoxic damage HIPK2 promotes apoptosis by modulating factors, directly or indirectly related to p53, such as the antiapoptotic

transcriptional corepressor CtBP [7], the p53 inhibitor MDM2 [32] and ΔNp63α [33]. HIPK2 participates in a pathway of UV-triggered CtBP clearance that results in cell death. HIPK2 phosphorylates CtBP at Ser-422 that induces protein degradation. Thus, HIPK2 knock-down Clomifene inhibits UV-induced CtBP-Ser-422 phosphorylation and degradation in p53-null H1299 lung cancer cells, confirming HIPK2 role in apoptosis also in cells lacking p53 [7, 34]. MDM2 is the main p53 negative regulator, it is an oncogene often upregulated in tumors and for these reasons many studies are devoted to the development of small molecules to inhibit MDM2 and restore p53 activity [11, 35]. HIPK2, by phosphorylating MDM2 for proteasomal degradation [36], may overcome the MDM2-induced p53 inactivation and restore p53 apoptotic activity [32]. On the other hand, an intriguing regulatory circuitry between MDM2 and HIPK2/p53 axis revealed that sublethal DNA damage leads to HIPK2 inhibition by a protein degradation mechanism involving p53-induced MDM2 activity [37]. These findings highlight a role for MDM2 to fine-tune the p53-mediated biological outcomes (that is, cell cycle arrest vs apoptosis) according to cell requirement.