STAT5 and Oct-1 Form a Stable Complex That Modulates Cyclin D1 Expression

Abstract

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.

ACKNOWLEDGMENTS

Fabrice Gouilleux, Itaru Matsumura, and Lothar Henninghausen are gratefully acknowledged for kind gifts of plasmids and antibodies and for helpful discussions. We thank Claire Francastel, Sylvie Gisselbrecht, Vincent Mignotte, and Paul-Henri Romeo for reading the manuscript and providing valuable comments and Frank Letourneur and Nicolas Lebrun for DNA sequencing.

This work was supported by a grant from the Ligue Nationale Contre le Cancer. S.C. is the recipient of a fellowship from the Ligue Contre le Cancer.