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

Nat Cell Biol. 2002 Jan;4(1):1-10. doi: 10.1038/ncb715.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Carrier Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oligonucleotides, Antisense
  • Pml protein, mouse
  • Promyelocytic Leukemia Protein
  • Protein Isoforms
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • PML protein, human
  • CREB-Binding Protein
  • CREBBP protein, human
  • Crebbp protein, mouse
  • HIPK2 protein, human
  • Hipk2 protein, mouse
  • Protein-Serine-Threonine Kinases