Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP

Cell. 2003 Oct 17;115(2):177-86. doi: 10.1016/s0092-8674(03)00802-x.

Abstract

Genetic knockout of the transcriptional corepressor CtBP in mouse embryo fibroblasts upregulates several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP. To identify pathways involved in this regulation, we screened a mouse embryo cDNA library with an E1A-CtBP complex and identified the homeodomain interacting protein kinase 2 (HIPK2), which had previously been linked to UV-directed apoptosis through its ability to phosphorylate p53. Expression of HIPK2 or exposure to UV irradiation reduced CtBP levels via a proteosome-mediated pathway. The UV effect was prevented by coexpression of kinase-inactive HIPK2 or reduction in HIPK2 levels via siRNA. Mutation of the residue phosphorylated by HIPK2 prevented UV- and HIPK2-directed CtBP clearance. Finally, reduction in CtBP levels, either by genetic knockout or siRNA, promoted apoptosis in p53-deficient cells. These findings provide a pathway for UV-induced apoptosis in cells lacking p53.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alcohol Oxidoreductases
  • Amino Acid Substitution
  • Animals
  • Apoptosis / genetics*
  • Apoptosis / radiation effects
  • COS Cells
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Carrier Proteins / radiation effects
  • Chlorocebus aethiops
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / radiation effects
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Serine / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Ultraviolet Rays

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Serine
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • HIPK2 protein, human
  • Hipk2 protein, mouse
  • Protein-Serine-Threonine Kinases