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J. Biol. Chem., Vol. 276, Issue 18, 15354-15361, May 4, 2001
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From the Insulin-like growth factor I (IGF-I) plays a
central role in skeletal growth by promoting bone cell replication and
differentiation. Prostaglandin E2 (PGE2)
and parathyroid hormone enhance cAMP production in cultured rat
osteoblasts and stimulate IGF-I expression through a transcriptional
mechanism mediated by cAMP-dependent protein kinase (PKA).
We previously showed that PGE2 activated the transcription factor CCAAT/enhancer-binding protein
Regulated Nuclear-Cytoplasmic Localization of
CCAAT/ Enhancer-binding Protein
in Osteoblasts*
,,
Oregon Health Sciences University, Molecular
Medicine Division, Department of Medicine, Portland,
Oregon 97201-3098, the § Oregon Health Sciences University,
Departments of Cell and Developmental Biology and Medicine, Portland,
Oregon 97201-3098, and the ¶ Yale University School of Medicine,
Section of Plastic Surgery, New Haven, Connecticut 06520-8041
(C/EBP) in osteoblasts and
induced its binding to a DNA element within the IGF-I promoter. We
report here that a PKA-dependent pathway stimulates nuclear translocation of C/EBP. Under basal conditions, C/EBP was
cytoplasmic but rapidly accumulated in the nucleus after
PGE2 treatment (t1/2 < 30 min).
Nuclear translocation occurred without concurrent protein synthesis and
was maintained in the presence of hormone. Nuclear localization
required PKA and was blocked by a dominant-interfering regulatory
subunit of the enzyme, even though C/EBP was not a PKA substrate.
Upon removal of hormonal stimulus, C/EBP quickly exited the nucleus
(t1/2 < 12 min) through a pathway blocked by
leptomycin B. Mutagenesis studies indicated that the basic domain of
C/EBP was necessary for nuclear localization and that the leucine
zipper region permitted full nuclear accumulation. We thus
define a pathway for PKA-mediated activation of C/EBP through its
regulated nuclear import.
*
This work was supported by National Institutes of Health
Grants 5-RO1-DK37449 (to P. R.), 1-RO1-DK56310 (to T. L. M.), and 5F32-DK09802 (to J. B.).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.
To whom correspondence should be addressed: Oregon Health
Sciences University, Molecular Medicine Division, 3181 S.W. Sam Jackson
Park Rd., Mail code NRC3, Portland, OR 97201-3098. Tel.: 503-494-0536;
Fax: 503-494-7368; E-mail: rotweinp@ohsu.edu.
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