The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage.
The promyelocytic leukemia (PML) gene, a tumor suppressor inactivated in acute promyelocytic leukemia (APL), regulates apoptosis induced by DNA damage. However, the molecular mechanisms by which PML modulates apoptosis following genotoxic stress are only partially elucidated. PML is essential for p53-dependent induction of programmed cell death upon gamma-irradiation through PML-nuclear body (NB)-mediated control of p53 acetylation. Here, we show that PML selectively regulates proapoptotic transcription factors upon different types of DNA damage. We find that Pml inactivation protects fibroblasts from UV-induced apoptosis in a p53-independent manner. We demonstrate that c-Jun is required for UV-induced apoptosis and that PML is essential for both c-Jun transcriptional activation and DNA binding upon UV radiation. We find that PML physically interacts with c-Jun and that upon UV radiation the PML-NBs reorganize into novel nuclear microspeckled structures (UV-NBs), where PML and c-Jun dynamically accumulate. These data identify a novel PML-dependent pathway for c-Jun transcriptional activation and induction of apoptosis in response to DNA damage and shed new light on the role of PML in tumor suppression.
Salomoni
Paolo
P
Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY, USA.
Bernardi
Rosa
R
Bergmann
Stephan
S
Changou
Austin
A
Tuttle
Sara
S
Pandolfi
Pier Paolo
PP
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects; D004622:Embryo, Mammalian / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000528:radiation effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins