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This version published online on February 17, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0426
A more recent version of this article appeared on July 1, 2005
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Submitted on October 20, 2004
Accepted on February 10, 2005

Thyroid Transcription Factor 1 Rescues PAX8/p300 Synergism Impaired by a Natural PAX8 Paired Domain Mutation with Dominant Negative Activity

HELMUT GRASBERGER, USANEE RINGKANANONT, PAULE LEFRANCOIS, MARC ABRAMOWICZ, GILBERT VASSART, and SAMUEL REFETOFF*

Departments of Medicine (H.G., U.R., S.R.), Pediatrics (S.R.), and Committee on Genetics (S.R.), The University of Chicago, Chicago, IL; Centre Hospitalier de la Region Annecienne (P.L.), Annecy, France; IRIBHM (M.A., G.V.) and Department of Genetics, Campus Erasme (G.V.), Universite Libre de Bruxelles, Brussels, Belgium

* To whom correspondence should be addressed. E-mail: refetoff{at}uchicago.edu.

Mutations in the paired domain transcription factor PAX8 are a rare cause of congenital hypothyroidism due to thyroid dysgenesis. We identified a novel and unique PAX8 mutation segregating in seven affected members of a three generations family. The mutation replaces an invariant serine residue within helix 2 of the paired DNA-binding domain for phenylalanine. The mutant protein (PAX8-S48F) does not induce the thyroglobulin promoter in non-thyroid cells, but displays almost half of wild type PAX8 activity in thyroid cells. PAX8-S48F shows no defect in expression, nuclear targeting or DNA-binding, and retains the ability to synergize with thyroid transcription factor 1 (TTF-1, NKX2.1). However, we found that in non-thyroid cells, the acetylation-independent synergism with the general transcriptional adaptor p300 is completely abrogated, suggesting that PAX8-S48F may be unable to efficiently recruit p300. Reconstitution experiments in non-thyroid cells reveal that TTF-1 can partially rescue PAX8-S48F/p300 synergism and thus reproduce the situation in thyroid cells. These functional characteristics result in a dominant negative effect of PAX8-S48F on co-expressed wild type PAX8 activity, which is not observed in paired domain mutations with DNA-binding defect. Our results describe the first dominant negative missense mutation in a paired domain and provide evidence for a crucial role of the p300 co-activator in mediating the functional synergism between PAX8 and TTF-1 in thyroid-specific gene expression.
Key words: Pax protein • TTF-1 • p300 • CBP • thyroglobulin • paired box • homeodomain • congenital hypothyroidism • thyroid dysgenesis




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