Cytoplasmic function of mutant promyelocytic leukemia (PML) and PML-retinoic acid receptor-α

Cristian Bellodi, Karin Kindle, Francesca Bernassola, David Dinsdale, Andrea Cossarizza, Gerry Melino, David Heery, Paolo Salomoni

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)14465-14473
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number20
DOIs
Publication statusPublished - May 19 2006

ASJC Scopus subject areas

  • Biochemistry

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