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PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in response to DNA damage.

The promyelocytic leukemia (PML) tumor suppressor protein, a central regulator of cell proliferation and apoptosis, is frequently fused to the retinoic acid receptor-alpha (RARalpha) in acute PML. Here we show the interaction of PML with another tumor suppressor protein, the serine/threonine kinase homeodomain-interacting protein kinase (HIPK2). In response to DNA damage, HIPK2 phosphorylates PML at serines 8 and 38. Although HIPK2-mediated phosphorylation of PML occurs early during the DNA damage response, the oncogenic PML-RARalpha fusion protein is phosphorylated with significantly delayed kinetics. DNA damage or HIPK2 expression leads to the stabilization of PML and PML-RARalpha proteins. The N-terminal phosphorylation sites contribute to the DNA damage-induced PML SUMOylation and are required for the ability of PML to cooperate with HIPK2 for the induction of cell death.

Pubmed ID: 19015637

Authors

  • Gresko E
  • Ritterhoff S
  • Sevilla-Perez J
  • Roscic A
  • Fröbius K
  • Kotevic I
  • Vichalkovski A
  • Hess D
  • Hemmings BA
  • Schmitz ML

Journal

Oncogene

Publication Data

February 5, 2009

Associated Grants

None

Mesh Terms

  • Carrier Proteins
  • Cell Death
  • Cells, Cultured
  • DNA Damage
  • Genes, Tumor Suppressor
  • Humans
  • Nuclear Proteins
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Stability
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • SUMO-1 Protein
  • Serine
  • Transcription Factors
  • Tumor Suppressor Proteins