THE THYROID-HORMONE RECEPTOR FUNCTIONS AS A LIGAND-OPERATED DEVELOPMENTAL SWITCH BETWEEN PROLIFERATION AND DIFFERENTIATION OF ERYTHROID PROGENITORS

The avian erythroblastosis virus (AEV) oncoprotein v-ErbA represents a mutated, oncogenic thyroid hormone receptor a (c-ErbA/TR alpha), v-Er bA cooperates with the stem cell factor-activated, endogenous receptor tyrosine kinase c-Kit to induce self-renewal and to arrest differenti ation of primary avian erythroblasts, the AEV transformation target ce lls, In this cooperation, v-ErbA substitutes for endogenous steroid ho rmone receptor function required for sustained proliferation of non-tr ansformed erythroid progenitors. In this paper, we propose a novel con cept of how v-ErbA transforms erythroblasts, Using culture media stric tly depleted from thyroid hormone (T3) and retinoids, the ligands for c-ErbA/TR alpha and its coreceptor RXR, we show that overexpressed, un liganded c-ErbA/TR alpha closely resembles v-ErbA in its activity on p rimary erythroblasts. In cooperation with ligand-activated c-Kit, c-Er bA/TR alpha causes steroid-independent, long-term proliferation and ti ghtly blocks differentiation. Activation of c-ErbA/ TR alpha by physio logical T3 levels causes the loss of self-renewal capacity and induces synchronous, terminal differentiation under otherwise identical condi tions, This T3-induced switch in erythroid progenitor development is c orrelated with a decrease of c-ErbA-associated histone deacetylase act ivity. Our results suggest that the crucial role of the mutations acti vating v-erbA as an oncogene is to 'freeze' c-ErbA/TR alpha in its non -liganded, repressive conformation and to facilitate its overexpressio n.