HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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-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.
AuthorsCristian Bellodi, Karin Kindle, Francesca Bernassola, David Dinsdale, Andrea Cossarizza, Gerry Melino, David Heery, Paolo Salomoni
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 20 Pg. 14465-73 (May 19 2006) ISSN: 0021-9258 [Print] United States
PMID16540467 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Neoplasm Proteins
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PML protein, human
Topics
  • Animals
  • COS Cells
  • Cell Differentiation
  • Cell Line
  • Chlorocebus aethiops
  • Cytoplasm (metabolism)
  • Humans
  • Models, Biological
  • Mutation
  • Mutation, Missense
  • Neoplasm Proteins (genetics)
  • Nuclear Proteins (genetics)
  • Promyelocytic Leukemia Protein
  • Protein Structure, Tertiary
  • Receptors, Retinoic Acid (genetics)
  • Retinoic Acid Receptor alpha
  • Transcription Factors (genetics)
  • Transcription, Genetic
  • Tumor Suppressor Proteins (genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: