Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways.
Signal transducer and activator of transcription (STAT) 5b-retinoic acid receptor (RAR) alpha is the fifth fusion protein identified in acute promyelocytic leukemia (APL). Initially described in a patient with all-trans retinoic acid (ATRA)-unresponsive disease, STAT5b-RARalpha resulted from an interstitial deletion on chromosome 17. To determine the molecular mechanisms of myeloid ... leukemogenesis and maturation arrest in STAT5b-RARalpha(+) APL and its unresponsiveness to ATRA, we examined the effect of STAT5b-RARalpha on the activity of myeloid transcription factors including RARalpha/retinoid X receptor (RXR) alpha, STAT3, and STAT5 as well as its molecular interactions with the nuclear receptor corepressor, SMRT, and nuclear receptor coactivator, TRAM-1. STAT5b-RARalpha bound to retinoic acid response elements (RAREs) both as a homodimer and as a heterodimer with RXRalpha and inhibited wild-type RARalpha/RXRalpha transactivation. Although STAT5b-RARalpha had no effect on ligand-induced STAT5b activation, it enhanced interleukin 6-induced STAT3-dependent reporter activity, an effect shared by other APL fusion proteins including promyelocytic leukemia-RARalpha and promyelocytic leukemia zinc finger (PLZF)-RARalpha. SMRT was released from STAT5b-RARalpha/SMRT complexes by ATRA at 10(-6) M, whereas TRAM-1 became associated with STAT5b-RARalpha at 10(-7) M. The coiled-coil domain of STAT5b was required for formation of STAT5b-RARalpha homodimers, for the inhibition of RARalpha/RXRalpha transcriptional activity, and for stability of the STAT5b-RARalpha/SMRT complex. Thus, STAT5b-RARalpha contributes to myeloid maturation arrest by binding to RARE as either a homodimer or as a heterodimer with RXRalpha resulting in the recruitment of SMRT and inhibition of RARalpha/RXRalpha transcriptional activity. In addition, STAT5b-RARalpha and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway.
Mesh Terms:
DNA-Binding Proteins, Dimerization, Drug Interactions, Drug Resistance, Humans, Leukemia, Promyelocytic, Acute, Milk Proteins, Nuclear Receptor Co-Repressor 2, Nuclear Receptor Coactivator 3, Oncogene Proteins, Fusion, Protein Structure, Tertiary, Receptors, Retinoic Acid, Repressor Proteins, Response Elements, Retinoid X Receptors, STAT3 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic, Transfection, Tretinoin, Tumor Cells, Cultured
DNA-Binding Proteins, Dimerization, Drug Interactions, Drug Resistance, Humans, Leukemia, Promyelocytic, Acute, Milk Proteins, Nuclear Receptor Co-Repressor 2, Nuclear Receptor Coactivator 3, Oncogene Proteins, Fusion, Protein Structure, Tertiary, Receptors, Retinoic Acid, Repressor Proteins, Response Elements, Retinoid X Receptors, STAT3 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic, Transfection, Tretinoin, Tumor Cells, Cultured
Blood
Date: Apr. 15, 2002
PubMed ID: 11929748
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