TRANSFORMATION OF HEMATOPOIETIC-CELLS BY THE SKI ONCOPROTEIN INVOLVESREPRESSION OF RETINOIC ACID RECEPTOR SIGNALING

The Ski oncogene has dramatic effects on the differentiation of severa l different cell types. It induces the differentiation of quail embryo cells into myoblasts and arrests the differentiation of chicken hemat opoietic cells. The mechanism that Ski uses to carry out these dispara te biological activities is unknown. However, we were struck by the si milarity of these effects to those of certain members of the nuclear h ormone receptor family, Both Ski and the thyroid hormone receptor-deri ved oncogene v-ErbA can arrest the differentiation of avian erythrobla sts, and v-Ski-transformed avian multipotent progenitor cells resemble murine hemato poietic cells that express a dominant-negative form of the retinoic acid receptor, RAR alpha, In this paper, we have tested t he hypothesis that v-Ski and its cellular homologue c-Ski exert their effects by interfering,vith nuclear hormone receptor induced transcrip tion. We demonstrate that Ski associates with the RAR complex and can repress transcription from a retinoic acid response element. The physi ological significance of this finding is demonstrated by the ability o f high concentrations of a RAR alpha-specific ligand to abolish v-Ski induced transformation of the multipotent progenitors. These results s trongly suggest that the ability of Ski to alter cell differentiation is caused in part by the modulation of RAR signaling pathways.