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J. Biol. Chem., Vol. 277, Issue 33, 29840-29846, August 16, 2002
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From the Bone morphogenetic protein (BMP) signaling
regulates body axis determination, apoptosis, and differentiation of
various types of cells including neuron, gut, and bone cells. However,
the molecules involved in such BMP regulation of biological events have
not been fully understood. Here, we examined the involvement of
Cas-interacting zinc finger protein (CIZ) in the modulation of
BMP2-induced osteoblastic cell differentiation. CIZ overexpression in
osteoblastic MC3T3E1 cells suppressed BMP2-enhanced expression of
alkaline phosphatase, osteocalcin, and type I collagen genes. Upstream
analyses revealed that CIZ overexpression also suppressed BMP2-induced
enhancement of the mRNA expression of Cbfa1, which is a critical
transcription factor for osteoblastic differentiation. BMP-induced
Smad1 and Smad5 activation of GCCG-mediated transcription was
blocked in the presence of CIZ overexpression. CIZ overexpression alone
in the absence of BMP2 moderately enhanced basal levels of Cbfa1 mRNA expression. CIZ overexpression also enhanced 1.8-kb Cbfa1 promoter activity in the absence of BMP2, whereas it suppressed the
promoter activity in the presence of BMP2. Finally, CIZ overexpression suppressed the formation of mineralized nodules in osteoblastic cell
cultures. These data indicate that CIZ is a novel type inhibitor of
BMP/Smad signaling.
Negative Regulation of Bone Morphogenetic Protein/Smad
Signaling by Cas-interacting Zinc Finger Protein in Osteoblasts*
,
,
,
,
**
Department of Molecular Pharmacology,
Medical Research Institute, Tokyo Medical and Dental University,
3-10 Kanda-Sunugadai 2-Chome Chiyoda-ku, Tokyo, 101 Japan, the
§ Department of Hematology and Oncology, and
¶ Department of Molecular Pathology, Graduate School of Medicine,
University of Tokyo, Tokyo, Japan, and the
Department
of Molecular Medicine, Osaka University Medical School,
Osaka, Japan
*
This research was supported by the grants-in-aid received
from the Japanese Ministry of Education (14207056, 14034214, 14028022, 12557123, 13045011, and 13216034), grants from NASDA, Japan Society for
Promotion of Science (Research for the Future Program, Genome Science),
and Tokyo Biochemistry Research Foundation.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.
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