STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression.
Signal transducer and activator of transcription 5 (STAT5) is activated by numerous cytokines that control blood cell development. STAT5 was also shown to actively participate in leukemogenesis. Among the target genes involved in cell growth, STAT5 had been shown to activate cyclin D1 gene expression. We now show that thrombopoietin-dependent activation of the cyclin D1 promoter depends on the integrity of a new bipartite proximal element that specifically binds STAT5A and -B transcription factors. We demonstrate that the stable recruitment of STAT5 to this element in vitro requires the integrity of an adjacent octamer element that constitutively binds the ubiquitous POU homeodomain protein Oct-1. We observe that cytokine-activated STAT5 and Oct-1 form a unique complex with the cyclin D1 promoter sequence. We find that STAT5 interacts with Oct-1 in vivo, following activation by different cytokines in various cellular contexts. This interaction involves a small motif in the carboxy-terminal region of STAT5 which, remarkably, is similar to an Oct-1 POU-interacting motif present in two well-known partners of Oct-1, namely, OBF-1/Bob and SNAP190. Our data offer new insights into the transcriptional regulation of the key cell cycle regulator cyclin D1 and emphasize the active roles of both STAT5 and Oct-1 in this process.
Magné
Sophie
S
Department of Hematology, Institut Cochin, INSERM U567, CNRS UMR 8104, Université René Descartes, 123 Boulevard Port-Royal, 75014 Paris, France.
Caron
Sandrine
S
Charon
Martine
M
Rouyez
Marie-Christine
MC
Dusanter-Fourt
Isabelle
I
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D019940:Genes, bcl-1; D051863:Host Cell Factor C1; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D051379:Mice; D008894:Milk Proteins; D050811:Octamer Transcription Factor-1; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor; D013926:Thrombopoietin / Q000494:pharmacology; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D016207:Cytokines; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; C497693:Hcfc1 protein, mouse; D051863:Host Cell Factor C1; D046911:Macromolecular Substances; D008894:Milk Proteins; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; C494166:Pou2f1 protein, mouse; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D004247:DNA; D013926:Thrombopoietin