The thyroid hormone receptor functions as a ligand-operated developmental switch between proliferation and differentiation of erythroid progenitors

• Published in: The EMBO journal 1998-08, Vol.17 (15), p.4291-4303
• Main Authors: Bauer, Anton, Mikulits, Wolfgang, Lagger, Gerda, Stengl, Gabi, Brosch, Gerald, Beug, Hartmut
• Format: Article
• Language: English
• Subjects: Animals; Avian myeloblastosis virus; Bone Marrow Cells - cytology; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Division - drug effects; Cell Division - genetics; Cell Division - physiology; Chickens; differentiation; Erythroblasts - cytology; Erythroblasts - enzymology; Erythroblasts - metabolism; erythropoiesis; Erythropoiesis - drug effects; Erythropoiesis - genetics; Gene Expression Regulation - drug effects; histone deacetylases; Histone Deacetylases - blood; Ligands; Proto-Oncogene Proteins c-kit - metabolism; Proto-Oncogene Proteins c-kit - physiology; Receptors, Thyroid Hormone - drug effects; Receptors, Thyroid Hormone - genetics; Receptors, Thyroid Hormone - metabolism; Receptors, Thyroid Hormone - physiology; Retinoids - pharmacology; thyroid hormone receptor; Triiodothyronine - metabolism; Triiodothyronine - pharmacology; v-ErbA
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/17.15.4291

The avian erythroblastosis virus (AEV) oncoprotein v‐ErbA represents a mutated, oncogenic thyroid hormone receptor α (c‐ErbA/ TRα). v‐ErbA cooperates with the stem cell factor‐activated, endogenous receptor tyrosine kinase c‐Kit to induce self‐renewal and to arrest differentiation of primary avian erythroblasts, the AEV transformation target cells. In this cooperation, v‐ErbA substitutes for endogenous steroid hormone receptor function required for sustained proliferation of non‐transformed erythroid progenitors. In this paper, we propose a novel concept of how v‐ErbA transforms erythroblasts. Using culture media strictly depleted from thyroid hormone (T3) and retinoids, the ligands for c‐ErbA/TRα and its co‐receptor RXR, we show that overexpressed, unliganded c‐ErbA/ TRα closely resembles v‐ErbA in its activity on primary erythroblasts. In cooperation with ligand‐activated c‐Kit, c‐ErbA/ TRα causes steroid‐independent, long‐term proliferation and tightly blocks differentiation. Activation of c‐ErbA/ TRα by physiological T3 levels causes the loss of self‐renewal capacity and induces synchronous, terminal differentiation under otherwise identical conditions. This T3‐induced switch in erythroid progenitor development is correlated with a decrease of c‐ErbA‐associated histone deacetylase activity. Our results suggest that the crucial role of the mutations activating v‐ erb A as an oncogene is to ‘freeze’ c‐ErbA/ TRα in its non‐liganded, repressive conformation and to facilitate its overexpression.