Cytoplasmic function of mutant promyelocytic leukemia (PML) and PML-retinoic acid receptor-alpha.
The promyelocytic leukemia (PML) tumor suppressor of acute promyelocytic leukemia (APL) regulates major apoptotic and growth-suppressive pathways. In APL, PML is involved in a chromosomal translocation generating the PML-retinoic acid receptor-alpha (RARalpha) fusion protein. Two missense mutations in the remaining PML alleles have been identified, which give rise to a truncated cytoplasmic PML protein (Mut PML). APL patients carrying these mutations display resistance to retinoic acid (RA) and very poor prognosis. Here we show that Mut PML associates with the cytoplasmic regions we refer to as PML-cytoplasmic bodies (PML-CBs). Mut PML interacts with PML-RARalpha in PML-CB and potentiates PML-RARalpha-mediated inhibition of RA-dependent transcription. Remarkably, Mut PML stabilizes PML-RARalpha and inhibits differentiation induced by pharmacological doses of RA. A mutant form of PML-RARalpha that accumulates in the cytoplasm inhibits RA-dependent transcription and differentiation, thus suggesting that cytoplasmic localization of PML-RARalpha may contribute to transformation. Finally, we show that the bcr3 PML-RARalpha form is predominantly cytoplasmic and accumulates in PML-CBs. Taken together, these findings reveal novel insights into the molecular mechanisms contributing to APL.
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom.
Cristian
C
Bellodi
Karin
K
Kindle
Francesca
F
Bernassola
David
D
Dinsdale
Andrea
A
Cossarizza
Gerry
G
Melino
David
D
Heery
Paolo
P
Salomoni
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000071156:Promyelocytic Leukemia Protein; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human