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.
Dong
Shuo
S
Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Tweardy
David J
DJ
D004268:DNA-Binding Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D019281:Dimerization; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000235:genetics*; D008894:Milk Proteins; D056985:Nuclear Receptor Co-Repressor 2; D056921:Nuclear Receptor Coactivator 3; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000187:drug effects / Q000378:metabolism; D020218:Response Elements; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D008894:Milk Proteins; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C456500:STAT5-RARalpha protein, human; C494095:STAT5B protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D056921:Nuclear Receptor Coactivator 3