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Nucleic Acids Research, Vol 26, Issue 9 2098-2104, Copyright © 1998 by Oxford University Press


ARTICLES

The activation function 2 domain of hepatic nuclear factor 4 is regulated by a short C-terminal proline-rich repressor domain

VP Iyemere, NH Davies and GG Brownlee
Chemical Pathology Unit, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.

Hepatic nuclear factor 4 (HNF4) is a transcription factor whose expression is crucial for mouse embryonic development, for liver- specific gene expression and for the prevention of one form of maturity- onset diabetes of the young. Its domain structure has been defined previously and is similar to other members of the nuclear receptor superfamily. A repressor domain has now been localised to a region of 14 amino acids (residues 428-441) near the C-terminus of HNF4 and is sufficient by itself to repress the activity of the activation function 2 (AF2) domain. Multiple mutations within this repressor domain enhance activity. Interestingly, this repressor domain shares homology with a repressor domain in the progesterone receptor. In a detailed mutagenesis study of the AF2 core, we demonstrate that L 366, which is conserved in the AF2 core between HNF4 and a number of orphan nuclear receptors, is essential for the full activity of the AF2 domain. Furthermore, a double mutation of E 363 and L 366 suggests that these residues might act in a cooperative manner.
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