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INSERM U 478, Faculté de Médecine Xavier Bichat, 75870 Paris Cedex 18, France
Aldosterone effects are mediated by the MR, which possesses the
same affinity for mineralocorticoids and glucocorticoids. In addition
to the existence of mechanisms regulating intracellular hormone
availability, we searched for human MR splice variants involved in
tissue-specific corticosteroid function. We have identified a new human
MR isoform, hMR
5,6, resulting from an alternative splicing event
skipping exons 5 and 6 of the human MR gene. hMR5,6 mRNAs are
expressed in several human tissues at different levels compared with
wild-type human MR, as shown by real time PCR. Introduction of a
premature stop codon results in a 75-kDa protein lacking the entire
hinge region and ligand binding domain. Interestingly, hMR5,6 is
still capable of binding to DNA and acts as a ligand-independent
transactivator, with maximal transcriptional induction corresponding to
approximately 30–40% of aldosterone-activated wild-type human MR.
Coexpression of hMR5,6 with human MR or human GR increases their
transactivation potential at high doses of hormone. Finally, hMR5,6
is able to recruit the coactivators, steroid receptor coactivator 1,
receptor interacting protein 140, and transcription intermediary factor
1
, which enhance its transcriptional activity.
Ligand-independent transactivation and enhancement of both wild-type MR
and GR activities by hMR5,6 suggests that this new variant might
play a role in modulating corticosteroid effects in target
tissues.
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