Editors' ChoiceApotosis

HIPK2 Regulates P53 Activity

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Science's STKE  08 Jan 2002:
Vol. 2002, Issue 114, pp. tw2
DOI: 10.1126/stke.2002.114.tw2

The tumor suppressor p53 can regulate apoptosis and cell proliferation by activating the expression of specific genes. Activated p53 localizes into promyelocytic leukemia nuclear bodies (PML-NBs), but the mechanism by which p53 is activated and recruited remains unclear. Two papers by Hofmann et al. and D'Orazi et al. shed light on how p53 is activated. Both groups found that the homeodomain-interacting protein kinase-2 (HIPK2) bound to p53 in vitro and in vivo. Genetic analyses suggested that amino acids 853 to 955 of HIPK2 and amino acids 295 to 390 of p53 contained the sites of interaction. The kinase activity of HIPK2 was not required for binding to p53, but was required for p53-dependent gene transcription. Phosphoamino acid analysis indicated that HIPK2 phosphorylated p53 on Ser46, a site known to be important for p53 activation. HIPK2 localized to PML-NBs, and this recruitment was enhanced by the overexpression of PML3, a protein known to reside in PML-NBs. Fluorescence assays showed that HIPK2, p53, PML3, and the cAMP-responsive element binding protein (CREB) binding protein (CBP) all localized within PML-NBs. HIPK2-dependent phosphorylation of p53 was necessary for subsequent acetylation of p53 by CBP, as demonstrated by a lack of acetylation of the S46A p53 mutant, which cannot be phosphorylated by HIPK2. Although a number of stimuli can effect the phosphorylation of p53 on Ser46, only UV treatment induced HIPK2-dependent phosphorylation of p53 and led to cellular apoptosis. other kinases are likely to phosphorylate p53 Ser46 under other conditions. Thus, the data indicate that HIPK2 is an important regulator of p53 activation in apoptosis and cell proliferation.

T. G. Hofmann, A. Möller, H. Sirma, H. Zentgraf, Y. Taya, W. Dröge, H. Will, M. L. Schmitz, Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nature Cell Biol. 4, 1-10 (2002). [Online Journal]

G. D'Orazi, B. Cecchinelli, T. Bruno, I. Manni, Y. Higashimoto, S. Saito, M. Gostissa, S. Coen, A. Marchetti, G. Del Sal, G. Piaggio, M. Fanciulli, E. Appella, S. Soddu, Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nature Cell Biol. 4, 11-19 (2002). [Online Journal]

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