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PMID: 8096643 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Functional inhibition of retinoic acid response by dominant negative retinoic acid receptor mutants.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 90 ·No. 7 ·1993-04-01 ·Pages 2989-93

Damm K, Heyman RA, Umesono K, Evans RM

Abstract

The diverse effects of retinoids on the development, growth, and homeostasis of vertebrate organisms are mediated in part by three distinct isoforms of retinoic acid receptors (RARs). These proteins, which are structurally and functionally closely related to thyroid hormone receptors and the oncogene product v-ErbA, regulate patterns of gene expression in target tissues. One approach to study the distinct effects of retinoic acid in cells is to subvert this activity of endogenous receptors by expression of dominant negative receptor derivatives. We demonstrate here that RAR alpha, RAR beta, and RAR gamma can be converted into potent negative transcriptional regulators that block wild-type RAR function. Furthermore, these mutant RARs, but not the wild-type receptors, actively repress the basal transcription level of target promoters. When expressed in transgenic mice, the most potent of these inhibitory receptor mutants is apparently able to disturb developmental processes by inducing a cleft palate in transgenic offspring.

Related Genes
v-erbA
MeSH Terms
Amino Acid Sequence Animals Binding, Competitive Carrier Proteins/drug effects,genetics,metabolism Cell Line Chloramphenicol O-Acetyltransferase/genetics,metabolism Cleft Palate/genetics Congenital Abnormalities/genetics Genes, Dominant Humans Kinetics Mice Mice, Transgenic Molecular Sequence Data Oncogene Proteins v-erbA Promoter Regions, Genetic Protein-Tyrosine Kinases/genetics Receptors, Retinoic Acid Receptors, Thyroid Hormone/genetics Recombinant Fusion Proteins/metabolism Retroviridae Proteins, Oncogenic/genetics Sequence Homology, Amino Acid Transfection Tretinoin/metabolism,pharmacology
Chemicals
Carrier Proteins Oncogene Proteins v-erbA Receptors, Retinoic Acid Receptors, Thyroid Hormone Recombinant Fusion Proteins Retroviridae Proteins, Oncogenic Tretinoin Chloramphenicol O-Acetyltransferase Protein-Tyrosine Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Damm K
Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037.
Heyman R A
Umesono K
Evans R M
References (37)
37 references, click to expand
  1. Retinoic acid receptor expression vector inhibits differentiation of F9 embryonal carcinoma cells.
    Genes Dev. 1989 Nov;3(11):1647-56 PMID: 2558044
  2. Cyclic AMP analogs and retinoic acid influence the expression of retinoic acid receptor alpha, beta, and gamma mRNAs in F9 teratocarcinoma cells.
    Mol Cell Biol. 1990 Jan;10(1):391-6 PMID: 2152965
  3. Expression of retinoic acid receptor genes in neural crest-derived cells during mouse facial development.
    FEBS Lett. 1990 May 7;264(1):71-4 PMID: 2159896
  4. v-erbA oncogene activation entails the loss of hormone-dependent regulator activity of c-erbA.
    Cell. 1990 Jun 15;61(6):1035-49 PMID: 1972036
  5. Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis.
    Development. 1990 Feb;108(2):213-22 PMID: 2161730
  6. Characterization of an autoregulated response element in the mouse retinoic acid receptor type beta gene.
    Proc Natl Acad Sci U S A. 1990 Jul;87(14):5392-6 PMID: 2164682
  7. Multiple cell type-specific proteins differentially regulate target sequence recognition by the alpha retinoic acid receptor.
    Cell. 1990 Nov 16;63(4):729-38 PMID: 2171781
  8. A functional retinoic acid receptor encoded by the gene on human chromosome 12.
    Mol Endocrinol. 1990 Jun;4(6):837-44 PMID: 2172793
  9. A dominant negative mutation of the alpha retinoic acid receptor gene in a retinoic acid-nonresponsive embryonal carcinoma cell.
    Mol Cell Biol. 1990 Dec;10(12):6445-53 PMID: 2174108
  10. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors.
    Cell. 1991 Jun 28;65(7):1255-66 PMID: 1648450
  11. A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR.
    Cell. 1991 Aug 9;66(3):555-61 PMID: 1651173
  12. Retinoic acid treatment alters the distribution of retinoic acid receptor-beta transcripts in the embryonic chick face.
    Development. 1991 Apr;111(4):1007-16 PMID: 1652423
  13. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements.
    Cell. 1991 Dec 20;67(6):1251-66 PMID: 1662118
  14. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha.
    Nature. 1992 Jan 23;355(6358):359-61 PMID: 1309942
  15. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently.
    Cell. 1992 Jan 24;68(2):377-95 PMID: 1310259
  16. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor.
    Cell. 1992 Jan 24;68(2):397-406 PMID: 1310260
  17. Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.
    Nature. 1992 Jan 30;355(6359):446-9 PMID: 1310351
  18. A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor.
    EMBO J. 1992 Mar;11(3):1015-23 PMID: 1347744
  19. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.
    Genes Dev. 1992 Mar;6(3):329-44 PMID: 1312497
  20. Retinoids and their targets in vertebrate development.
    Curr Opin Cell Biol. 1991 Dec;3(6):928-34 PMID: 1667579
  21. An hydroxylapatite batch assay for the quantitation of 1alpha,25-dihydroxyvitamin D3-receptor complexes.
    Anal Biochem. 1979 Jan 15;92(2):314-23 PMID: 443532
  22. Retinoic acid embryopathy.
    N Engl J Med. 1985 Oct 3;313(14):837-41 PMID: 3162101
  23. Teratogen update: vitamin A congeners.
    Teratology. 1986 Jun;33(3):355-64 PMID: 3461576
  24. Isotretinoin embryopathy and the cranial neural crest: an in vivo and in vitro study.
    J Craniofac Genet Dev Biol. 1986;6(3):211-22 PMID: 3464614
  25. Epithelial-mesenchymal interactions in the development of chick facial primordia and the target of retinoid action.
    Development. 1987 Mar;99(3):341-51 PMID: 3653006
  26. A human retinoic acid receptor which belongs to the family of nuclear receptors.
    Nature. 1987 Dec 3-9;330(6147):444-50 PMID: 2825025
  27. Identification of a receptor for the morphogen retinoic acid.
    Nature. 1987 Dec 17-23;330(6149):624-9 PMID: 2825036
  28. Identification of a second human retinoic acid receptor.
    Nature. 1988 Apr 28;332(6167):850-3 PMID: 2833708
  29. Characterization of the hormone-binding domain of the chicken c-erbA/thyroid hormone receptor protein.
    EMBO J. 1988 Jan;7(1):155-9 PMID: 3359993
  30. A new retinoic acid receptor identified from a hepatocellular carcinoma.
    Nature. 1988 Jun 16;333(6174):669-72 PMID: 2836738
  31. Multiple and cooperative trans-activation domains of the human glucocorticoid receptor.
    Cell. 1988 Dec 2;55(5):899-906 PMID: 3191531
  32. Retinoic acid and thyroid hormone induce gene expression through a common responsive element.
    Nature. 1988 Nov 17;336(6196):262-5 PMID: 2848197
  33. Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist.
    Nature. 1989 Jun 22;339(6226):593-7 PMID: 2733791
  34. Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin.
    Nature. 1989 Jun 29;339(6227):714-7 PMID: 2544807
  35. A third human retinoic acid receptor, hRAR-gamma.
    Proc Natl Acad Sci U S A. 1989 Jul;86(14):5310-4 PMID: 2546152
  36. Positive and negative regulation of gene transcription by a retinoic acid-thyroid hormone receptor heterodimer.
    Cell. 1989 Nov 17;59(4):697-708 PMID: 2555064
  37. Nuclear receptor that identifies a novel retinoic acid response pathway.
    Nature. 1990 May 17;345(6272):224-9 PMID: 2159111
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.90.7.2989
Published
1993-04-01
Pages
2989-93
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC46222
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.90.7.2989 PMC Full Text View journal details
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