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

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.

Pubmed ID: 11740489

Authors

  • Hofmann TG
  • Möller A
  • Sirma H
  • Zentgraf H
  • Taya Y
  • Dröge W
  • Will H
  • Schmitz ML

Journal

Nature cell biology

Publication Data

January 7, 2002

Associated Grants

None

Mesh Terms

  • Animals
  • Apoptosis
  • CREB-Binding Protein
  • Carrier Proteins
  • Cell Division
  • Cell Nucleus
  • Enzyme Activation
  • Genes, Tumor Suppressor
  • Humans
  • Mice
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oligonucleotides, Antisense
  • Protein Binding
  • Protein Isoforms
  • Protein-Serine-Threonine Kinases
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Ultraviolet Rays