A cytoplasmic PML mutant inhibits p53 function.
The promyelocytic leukaemia gene (Pml) is a tumor suppressor identified in acute promyelocytic leukaemia (APL), where it is fused to RAR alpha gene as a result of the chromosomal translocation t(15;17). Pml encodes both nuclear and cytoplasmic isoforms. While nuclear PML has been intensively investigated, cytoplasmic PML proteins are less characterized. PML nuclear isoforms (nPML) are the essential components of subnuclear structures referred to as PML nuclear bodies (PML-NB). In response to cellular insults such as DNA damage and oncogenic activation, nPML modulates p53 activity through CBP-mediated acetylation and activates its pro-apoptotic and growth suppressive functions. Two missense mutations resulting in truncated PML cytoplasmic proteins (Mut PML) have been identified in aggressive APL cases. Here we report that cytoplasmic PML is able to induce the relocation of nPML to the cytoplasm, thus reducing the number of PML-NBs. Remarkably, Mut PML inhibits p53 transcriptional, growth suppressive, and apoptotic functions, thus suggesting that cytoplasmic expression of PML has an impact on survival through inhibition of nuclear PML. Overall our findings shed new light on the role of PML cytoplasmic proteins in the regulation of p53.
Bellodi
Cristian
C
MRC Toxicology Unit, Leicester, UK.
Kindle
Karin
K
Bernassola
Francesca
F
Cossarizza
Andrea
A
Dinsdale
David
D
Melino
Gerry
G
Heery
David
D
Salomoni
Paolo
P
D017209:Apoptosis; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human