The A/B domain of truncated retinoic acid receptors can block differentiation and promote features of malignancy

Aneskievich, B.J.; Fuchs, E.; Aneskievich, B.J; Fuchs, E

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The A/B domain of truncated retinoic acid receptors can block differentiation and promote features of malignancy

Aneskievich, B.J.; Fuchs, E.

Journal of Cell Science 108: 195-205

1995

ISSN/ISBN: 0021-9533

PMID: 7537744

Accession: 009528895

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Summary

Recently, we discovered that stable introduction of a carboxyl-terminally truncated retinoic acid receptor gamma (tRAR gamma) into an epidermal keratinocyte line blocked the ability of these cells to differentiate, as judged by their failure to express late markers of squamous differentiation. We now demonstrate a correlation between the level of residual endogenous RAR activity of tRAR gamma-expressing keratinocyte lines and degree of terminal differentiation. Mutagenesis studies localize the effects to the A/B subdomain of the truncated receptor. Despite tRAR gamma's capacity to interfere with RAR-mediated transactivation of retinoic acid response elements (RAREs) in keratinocytes, the effects of the truncated receptor are independent of its ability to bind DNA and directly interact with endogenous RARs. tRAR alpha also inhibits RARE-mediated gene expression in keratinocytes, even though its full-length counterpart enhances RARE activity in these cells. Intriguingly, both tRAR gamma and RAR gamma suppress keratin promoter activity in epidermal cells, although for tRAR gamma, the effect is mediated through the A/B domain whereas for RAR gamma, the effects require DNA binding. Taken together, these findings suggest that the truncation allows for new and aberrant interactions with transcriptional proteins/cofactors that participate in governing RARE activity. This discovery may have relevance in tumorigenesis, where genetic lesions can result in mutant RARs or in loss of receptor expression.

The A/B domain of truncated retinoic acid receptors can block differentiation and promote features of malignancy

Aneskievich, B.J.; Fuchs, E.

Journal of Cell Science 108: 195-205

1995

Full-Text Article emailed within 1 workday

Summary

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