PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in response to DNA damage.
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Gresko E, Ritterhoff S, Sevilla-Perez J, Roscic A, Frobius K, Kotevic I, Vichalkovski A, Hess D, Hemmings BA, Schmitz ML
PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in response to DNA damage.
Oncogene. 2009 Feb 5;28(5):698-708. doi: 10.1038/onc.2008.420. Epub 2008 Nov 17.
- PubMed ID
- 19015637 [ View in PubMed]
- Abstract
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.