TY - JOUR
T1 - Cytoplasmic function of mutant promyelocytic leukemia (PML) and PML-retinoic acid receptor-α
AU - Bellodi, Cristian
AU - Kindle, Karin
AU - Bernassola, Francesca
AU - Dinsdale, David
AU - Cossarizza, Andrea
AU - Melino, Gerry
AU - Heery, David
AU - Salomoni, Paolo
PY - 2006/5/19
Y1 - 2006/5/19
N2 - 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-α (RARα) 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-RARα in PML-CB and potentiates PML-RARα-mediated inhibition of RA-dependent transcription. Remarkably, Mut PML stabilizes PML-RARα and inhibits differentiation induced by pharmacological doses of RA. A mutant form of PML-RARα that accumulates in the cytoplasm inhibits RA-dependent transcription and differentiation, thus suggesting that cytoplasmic localization of PML-RARα may contribute to transformation. Finally, we show that the bcr3 PML-RARα form is predominantly cytoplasmic and accumulates in PML-CBs. Taken together, these findings reveal novel insights into the molecular mechanisms contributing to APL.
AB - 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-α (RARα) 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-RARα in PML-CB and potentiates PML-RARα-mediated inhibition of RA-dependent transcription. Remarkably, Mut PML stabilizes PML-RARα and inhibits differentiation induced by pharmacological doses of RA. A mutant form of PML-RARα that accumulates in the cytoplasm inhibits RA-dependent transcription and differentiation, thus suggesting that cytoplasmic localization of PML-RARα may contribute to transformation. Finally, we show that the bcr3 PML-RARα form is predominantly cytoplasmic and accumulates in PML-CBs. Taken together, these findings reveal novel insights into the molecular mechanisms contributing to APL.
UR - http://www.scopus.com/inward/record.url?scp=33744943554&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33744943554&partnerID=8YFLogxK
U2 - 10.1074/jbc.M600457200
DO - 10.1074/jbc.M600457200
M3 - Article
C2 - 16540467
AN - SCOPUS:33744943554
VL - 281
SP - 14465
EP - 14473
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 20
ER -