essential for p53 function. The folding of p53 depends on the presence of zinc, and HIPK2 plays a role in zinc regulation. Consequently, the absence of HIPK2 leads to p53 misfolding. HIPK2 indirectly enhances p53 activity by phosphorylating negative regulators of p53, such as CtBP1 and Mdm2, leading to their degradation by the proteasome. HIPK2 also has the ability to regulate cellular response to reactive oxygen species by regulating the expression of both oxidant and antioxidant genes. Regulation HIPK2 is regulated by other proteins, as well as cellular conditions and post-translational modifications. Positive Under conditions of DNA damage, HIPK2 is stabilized and subject to positive regulation. The activity of HIPK2 is increased through the action of caspase 6. Caspase 6 cleaves HIPK2 at residue D916 and D977. As a result, the auto-inhibitory domain is removed and the activity of HIPK2 increases. HIPK2 activity can also be increased through the action of checkpoint kinases. These kinases phosphorylate HIPK2 associated ubiquitin ligases and prevent their binding to HIPK2. As a result, the degradation of HIPK2 through the ubiquitin proteasome pathway is inhibited. In conditions of oxidative stress, sumoylation of HIPK2 prevents acetylation, and as a result maintains its function in facilitating apoptosis. Under normal physiological conditions however, acetylation of HIPK2 by a protein called p300 again stabilizes HIPK2 but, increases its ability to induce apoptosis. Phosphorylation of HIPK2 at residues T880 and S882, via another kinase or through auto-phosphorylation, leads to the recruitment of PIN1 and stabilization of HIPK2. This results in increased apoptotic function of HIPK2. Negative Under regular conditions HIPK2 is unstable and is subject to negative regulation. HIPK2 is subject to regulation by the ubiquitin proteasome pathway, in which ubiquitin ligases bind to HIPK2, leading to polyubiquitination at the K1182 residue, localization to the proteasome and subsequent degradation of the protein. leads to protein degradation. The PEST sequence found in HIPK2 is also linked to protein degradation. HIPK2 activity can also be down regulated by the protein HMGA1, which transports it back to the cytoplasm. In conditions of oxidative stress sumoylation of HIPK2 is discouraged and acetylation is promoted, resulting in its stabilization and the inhibition of its ability to facilitate apoptosis. p53 p53 regulates HIPK2 using both positive and negative mechanisms. p53 binds to the third intron of the caspase 6 gene, and promotes the activation of the gene. Caspase 6 in turn activates HIPK2. Conversely, p53 down