PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors.
Fiche publication
Date publication
février 1994
Journal
Proceedings of the National Academy of Sciences of the United States of America
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUIDEZ Fabien
Tous les auteurs :
Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY, Degos L, Zelent A, Waxman S, Chomienne C
Lien Pubmed
Résumé
Recently, we described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor alpha (RAR alpha). We have now cloned cDNAs encoding PLZF-RAR alpha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RAR alpha and PLZF(B)-RAR alpha fusion proteins like the PML-RAR alpha protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RAR alpha in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RAR alpha transactivation activity was obtained even with a very low PLZF-RAR alpha-expressing plasmid concentration. A "dominant negative" effect was observed when PLZF-RAR alpha fusion proteins were cotransfected with vectors expressing RAR alpha and retinoid X receptor alpha (RXR alpha). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR alpha fusion proteins in the molecular pathogenesis of APL.
Mots clés
Amino Acid Sequence, Animals, Cell Line, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 17, Cloning, Molecular, Genetic Variation, Haplorhini, Humans, Leukemia, Promyelocytic, Acute, drug therapy, Molecular Sequence Data, Neoplasm Proteins, genetics, Receptors, Retinoic Acid, genetics, Recombinant Fusion Proteins, genetics, Transcriptional Activation, drug effects, Transfection, Translocation, Genetic, Tretinoin, pharmacology, Zinc Fingers, genetics
Référence
Proc Natl Acad Sci U S A. 1994 02 1;91(3):1178-82