Affinity labelling and cloning of steroid and thyroid hormone receptors / edited by H. Gronemeyer.

Date:
[1988]
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Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Credit: Affinity labelling and cloning of steroid and thyroid hormone receptors / edited by H. Gronemeyer. Source: Wellcome Collection.

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    Ch. 17] Characterization of a с-егЬД-thyroid hormone receptor cDNA 315 nuclei from various tissues, gave no evidence of multiple receptors (Oppenheimer and Samuels, 1983). The recent results are surprising, particularly in view of the fact that there appears to be only one receptor for each of the steroid hormones. However, thyroid hormone has very diverse effects on gene expression, cell metabolism and differentiation, and it is possible that different receptors have distinct functions in these processes. The isolation of cDNAs for these receptors will undoubtedly facilitate an understanding and dissection of the broad biological effects of thyroid hormone. Our data show that the \-erbA protein represents a ligand independent form of the thyroid hormone receptor. The fact that both the deletion in \-erbA and the point mutations are required for abolishing hormone binding suggests that they have accumulated gradually, and that the acquisition of hormone independence has increased the oncogenic activity of \-erbA. Unpublished data (H. Beug ad U. Gehring) also demonstrate that the \-erbA protein binds DNA, suggesting that it acts like the thyroid hormone receptor by binding to regulatory elements of specific target genes. The nucleotide sequences recognized by \-erbA might, however, be distinct from those binding to the c-erbA protein, since the viral protein contains two amino acid substitutions in its putative DNA binding domain. In addition, the \-erbA protein might constitutively either up or down regulate the expression of its target genes. If their expression (or, alternatively, absence thereof) is important for differentiation of erythroblasts, the effects of \-erbA on erythroblasts are readily explained. A study of the synthesis of ion transporters in AEV transformed erythroblasts appears worthwhile, since v- erbA affects the ionic requirements of erythroblast growth, and thyroid hormone is known to increase synthesis of the Na-K ATPase. ACKNOWLEDGMENTS I thank my colleagues and coworkers Hartmut Beug, Юаи8 Damm, Thomas Graf, Alberto Munoz and Jan Sap for rewarding discussions and generous disclosure of unpublished data. REFERENCES Damm, К., Beug, H., Graf, T. and Vennström, В. (1987) А single point mutation in erb A restores the erythroid transforming potential of a mutant avian erythro¬ blastosis virus (AEV) defective in both erb A and erbB oncogenes. EM BO J. 6, 375-382. Dayton, A. I., Seiden, J. R., Laws, G., Dorney, D. J., Finan, J., Tripputi, P., Emanuel, B. S., Rovera, G.,Nowell,P. C. andGroce, C. M. (1984) Ahumanc- erbA oncogene homologue is closely proximal to the chromosome 17 breakpoint in acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA 81, 4495-4499. Frykberg, L., Palmieri, S., Beug, H., Graf, T., Hayman, M. J. and Vennström, В. (1983) Transforming capacities of avian erythroblastosis virus mutants deleted in the erb A or erbB oncogenes. Cell 32, 227-238. Graf, T. and Beug, H. (1978) Avian leukemia viruses: Interaction with their target cells in vivo and in vitro. Biochim. Biophys. Acta 516, 269-299.