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J. Biol. Chem., Vol. 277, Issue 25, 22902-22908, June 21, 2002
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From the Department of Medical Biochemistry, Institute of Basic
Medical Sciences, University of Oslo, N-0317 Oslo,
§ Medical Genetics, Department of Medical Biochemistry,
Göteborg University, SE 405 30 Göteborg, and
¶ Department of Biochemistry, Hamamatsu University School of
Medicine, 1-20-1 Handa-yama, Hamamatsu 431-3192, Japan
We have reported recently that mice
overexpressing the forkhead/winged helix transcription factor
FOXC2 are lean and show increased responsiveness to insulin
due to sensitization of the
Mechanisms of FOXC2- and FOXD1-mediated
Regulation of the RI
Subunit of cAMP-dependent
Protein Kinase Include Release of Transcriptional Repression and
Activation by Protein Kinase B and cAMP*
,,
, and
-adrenergic cAMP-PKA+
pathway and increased levels of the RI
subunit of
cAMP-dependent protein kinase (PKA) (Cederberg,
A., Grønning, L. M., Ahren, B., Taskén, K., Carlsson,
P., and Enerbäck, S. (2001) Cell 106, 563-573). In this present study, we reveal that FOXC2 and
a related factor, FOXD1, specifically activate the 1b
promoter of the RI gene in adipocytes and testicular
Sertoli cells, respectively. By deletional mapping, we discovered
two different mechanisms by which the Fox proteins activated expression
from the RI1b promoter. In 3T3-L1 adipocytes, an upstream region
represses promoter activity under basal conditions. Bandshift
experiments indicate that overexpression of FOXC2 promotes
the release of a potential repressor from this region. In Sertoli
cells, sequences downstream of the transcription start sites mediate
the activating effect of FOXD1, and protein kinase
B/Akt1 strongly induces this effect. Furthermore, we show that an
inactive FOXD1 mutant lowers the cAMP-mediated induction of
the RI1b reporter construct. In summary, winged helix transcription
factors of the FOXC/FOXD families function as regulators of
the RI subunit of PKA and may integrate hormonal signals acting
through protein kinase B and cAMP in a cell-specific manner.
*
This work was supported by the Norwegian Cancer Society, the
Program for Advanced Studies in Medicine, the Norwegian Research Council, Anders Jahres Foundation, Novo Nordic Research Foundation Committee, the Swedish Medical Research Foundation, The Arne and IngaBritt Lundberg Foundation, the Juvenile Diabetes Foundation, the
Wallenberg Foundation, Amersham Biosciences, The Upjohn Co., and a
Junior Individual Grant from the Swedish Foundation for Strategic
Research (to S. E.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
Present address: Oslo Urological University Clinic, Aker
University Hospital, N-0514 Oslo, Norway.
**
To whom correspondence should be addressed: Dept. of Medical
Biochemistry, Inst. of Basic Medical Sciences, University of Oslo,
P. O. Box 1112 Blindern, N-0317 Oslo, Norway. Tel.: 4722851454; Fax:
4722851497; E-mail: kjetil.tasken@basalmed.uio.no.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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