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Submitted on August 19, 2003
Accepted on March 10, 2004
Division of Biochemistry, Faculty of Medicine, Campus Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
* To whom correspondence should be addressed. E-mail: frank.claessens{at}med.kuleuven.ac.be.
The androgen receptor (AR) can be SUMOylated in its amino-terminal domain at lysines 385 and 511. This SUMOylation is responsive to several agonists, but is not induced by the pure antagonist hydroxyflutamide. We show that the main site of interaction of Ubc9, the SUMO-1 conjugating enzyme, resides in the transcription activation unit tau-5.
Overexpression of SUMO-1 represses the AR-mediated transcription and this effect is abolished after mutating both SUMO-1 acceptor sites. On the other hand, the mutation of lysine 385 clearly affects the cooperativity of the receptor on multiple hormone response elements. Lysine 511 is not implicated in this function. Surprisingly, these effects on cooperativity clearly depend on the nature of the response elements. When selective AREs, which are organized as direct repeats of 5'-TGTTCT-3'-like sequences, were tested the lysine 385 mutation did not increase the androgen response. Point mutations changing the direct repeat elements into inverted repeat elements restored the effects of the lysine 358 mutation on cooperativity. In conclusion, SUMOylation of the AR might have a differential function in the control of cooperativity, depending on the conformation of the AR-dimer bound to DNA.
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