Gann, A. A., Gates, P. B., Stark, D., Brockes, J. P. (June 1996) Receptor isoform specificity in a cellular response to retinoic acid. Proceedings of the Royal Society B: Biological Sciences, 263 (1371). pp. 729-34. ISSN 0962-8452 (Print)0962-8452
Abstract
The effects of retinoic acid on cell proliferation, differentiation and patterning are thought to be mediated by the various retinoic acid receptors. Different receptor types are encoded by distinct genes (alpha, beta, and gamma), whereas various isoforms within each type are encoded by splicing variants resulting from the use of alternative promoters. The only region that differs between isoforms is the N-terminal A region containing a transcriptional activating domain. It has been proposed that these alternative A regions confer distinct activities on the receptors, thus allowing each to mediate specific effects of retinoic acid, but it has been difficult to demonstrate such isoform specificity as most cells express a number of different retinoic acid receptors. In an attempt to test whether different isoforms can mediate distinct biological effects we are focusing on retinoic-acid-dependent growth inhibition of newt limb cells. We have constructed chimaeric receptors in which the retinoic acid binding domain of each of five newt retinoic acid receptors has been replaced with a thyroid hormone (T3) binding domain. These constructs were introduced individually into cells whose growth rate was then measured in the presence of T3. The chimaeric alpha 1 receptor mediated T3-dependent inhibition of proliferation that was comparable to that given by retinoic acid, whereas the alpha 2 isoform had no activity in this assay, nor did the delta 1A, delta 1B and Delta 2 receptors. When the A region was deleted from the alpha 1 chimaera it remained a potent T3-dependent transcriptional activator, but no longer mediated T3-dependent growth inhibition. In contrast, when the A region of alpha 1 was transferred to a delta chimaeric receptor, the resulting molecule was fully active in T3-dependent growth inhibition. This is the first direct evidence for isoform specificity in a biological response to retinoic acid, and demonstrates that the specificity of this response is confined to the A region.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Alternative Splicing Animals Base Sequence Cell Division/drug effects Cell Line DNA Primers/genetics Molecular Sequence Data Plasmids/genetics Receptors, Retinoic Acid/*drug effects/*genetics/metabolism Recombinant Fusion Proteins/genetics/metabolism Salamandridae Transfection Tretinoin/*pharmacology Triiodothyronine/metabolism/pharmacology |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein receptor |
| CSHL Authors: | |
| Communities: | School of Biological Sciences > SBS Administration |
| Depositing User: | Matt Covey |
| Date: | 22 June 1996 |
| Date Deposited: | 23 Jun 2014 18:54 |
| Last Modified: | 09 Sep 2021 18:48 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30332 |
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