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The thyroid hormone receptor functions as a ligand-operated developmental switch between proliferation and differentiation of erythroid progenitors.
- Source :
-
The EMBO journal [EMBO J] 1998 Aug 03; Vol. 17 (15), pp. 4291-303. - Publication Year :
- 1998
-
Abstract
- The avian erythroblastosis virus (AEV) oncoprotein v-ErbA represents a mutated, oncogenic thyroid hormone receptor alpha (c-ErbA/ TRalpha). 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/TRalpha and its co-receptor RXR, we show that overexpressed, unliganded c-ErbA/ TRalpha closely resembles v-ErbA in its activity on primary erythroblasts. In cooperation with ligand-activated c-Kit, c-ErbA/ TRalpha causes steroid-independent, long-term proliferation and tightly blocks differentiation. Activation of c-ErbA/ TRalpha 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-erbA as an oncogene is to 'freeze' c-ErbA/ TRalpha in its non-liganded, repressive conformation and to facilitate its overexpression.
- Subjects :
- Animals
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
Erythroblasts enzymology
Erythroblasts metabolism
Gene Expression Regulation drug effects
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
Retinoids pharmacology
Triiodothyronine metabolism
Triiodothyronine pharmacology
Erythroblasts cytology
Erythropoiesis drug effects
Erythropoiesis genetics
Receptors, Thyroid Hormone metabolism
Receptors, Thyroid Hormone physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0261-4189
- Volume :
- 17
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 9687498
- Full Text :
- https://doi.org/10.1093/emboj/17.15.4291