title: Physical interaction between retinoic acid receptor and the oncoprotein myb inhibits retinoic acid-dependent transactivation.
abstract: The c-myb protooncogene is predominantly expressed in hematopoietic cells and plays a vital role in hematopoiesis. Retinoic acid (RA) is able to induce differentiation of several hematopoietic cells. This differentiation is linked to decreased c-myb expression, suggesting that retinoid receptors (RAR/RXR) may down-regulate c-myb gene expression. Furthermore, recent data indicate that RAR inhibits the function of the Myb protein itself. In addition, the Myb-Ets oncogenic fusion protein has been shown to inhibit transcriptional activation by RAR and thyroid hormone receptor. Myb-Ets also antagonizes the biological response of erythrocytic progenitor cells to RA and thyroid hormone. This prompted us to investigate a possible cross talk between RAR and Myb. Here, we demonstrate that RA inhibits the expression of the endogenous Myb target gene tom-1. Conversely, Myb functions as a potent inhibitor of RA-induced biological responses. Functional analysis of Myb mutants in transfection studies revealed that the Myb DNA-binding domain (DBD) is necessary for repression whereas the transactivation domain is dispensable. Furthermore, we show that v-Myb and RAR interact in vitro and in vivo. This interaction requires the DBD of RAR. In contrast, glutathione S-transferase-pulldown assays with v-Myb mutants indicate that the DBD and the C terminus of Myb directly interact with RAR. Our results suggest that the physical interaction between Myb and RAR may play a role in the regulation of hematopoietic gene expression.
authors.affiliation: Institut für Experimentelle Krebsforschung, Klinik für Tumorbiologie an der Universität Freiburg, Breisacherstrasse 117, 79106 Freiburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Pfitzner
authors.forename: J
authors.initials: J
authors.lastname: Kirfel
authors.forename: P
authors.initials: P
authors.lastname: Becker
authors.forename: A
authors.initials: A
authors.lastname: Rolke
authors.forename: R
authors.initials: R
authors.lastname: Schüle
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D020626:Oncogene Proteins v-myb; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020598:Proto-Oncogene Proteins c-myb; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D020626:Oncogene Proteins v-myb; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D015682:Retroviridae Proteins, Oncogenic; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D004247:DNA