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.
Gresko
E
E
Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.
Ritterhoff
S
S
Sevilla-Perez
J
J
Roscic
A
A
Fröbius
K
K
Kotevic
I
I
Vichalkovski
A
A
Hess
D
D
Hemmings
B A
BA
Schmitz
M L
ML
D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D025842:SUMO-1 Protein / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
D002352:Carrier Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D025842:SUMO-1 Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D012694:Serine; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases