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The thyroid hormone receptor functions as a ligand‐operated developmental switch between proliferation and differentiation of erythroid progenitors
Author(s) -
Bauer Anton,
Mikulits Wolfgang,
Lagger Gerda,
Stengl Gabi,
Brosch Gerald,
Beug Hartmut
Publication year - 1998
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/17.15.4291
Subject(s) - biology , thyroid hormone receptor , cellular differentiation , microbiology and biotechnology , thyroid hormone receptor beta , receptor , progenitor cell , nuclear receptor , transcription factor , stem cell , hormone receptor , biochemistry , genetics , gene , cancer , breast cancer
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.