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J. Biol. Chem., Vol. 277, Issue 21, 18860-18867, May 24, 2002
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From the The chondrogenesis process requires
the ordered proliferation and differentiation of chondrocytes.
Insulin-like growth factor-binding protein (IGFBP)-3, well
characterized as the carrier of insulin-like growth factor (IGF), has
been reported to have intrinsic bioactivity that is independent of IGF
binding. The mechanisms involved in this IGF-independent action are
still unclear. Using the RCJ3.1C5.18 chondrogenic cells, which in
culture progresses from undifferentiated to terminally differentiated
chondrocytes, we have shown previously that IGFBP-3 has an
IGF-independent, antiproliferative effect in undifferentiated and early
differentiated but not in terminally differentiated chondrocytes. In
the present study, cDNA microarray analysis was used to screen for
genes: 1) that were regulated by IGFBP-3 in early but not in terminally
differentiated chondrocytes; 2) that were regulated specifically by
IGFBP-3, but not by IGF-I; and 3) whose regulation was abolished by
coincubation of IGFBP-3 with IGF-I. Signal transducer and activator of
transcription (STAT)-1 was the gene that, fulfilling the screening
criteria, exhibited the greatest up-regulation by IGFBP-3 (>40-fold).
STAT-1 gene up-regulation was confirmed by Northern analysis of cells
treated with IGFBP-3 or transfected with an IGFBP-3 expression vector. Remarkably, similar results were obtained when cells were transfected with an IGFBP-3 mutant unable to bind IGFs, definitively demonstrating the IGF-independent action of IGFBP-3. Consistent with the
up-regulation of STAT-1 mRNA, IGFBP-3 also increased STAT-1 protein
expression. Furthermore, both IGFBP-3 and the IGFBP-3 mutant induced
STAT-1 phosphorylation and its nuclear localization. An antisense
STAT-1 oligonucleotide abolished the IGF-independent cell apoptosis
induced by IGFBP-3. We have demonstrated that STAT-1 is a major
intracellular signaling and transcriptional target of the
IGF-independent apoptotic effect of IGFBP-3 in chondrogenesis.
Identification of STAT-1 as a Molecular Target of IGFBP-3
in the Process of Chondrogenesis*
§¶,
,,, Department of Pediatrics, Vanderbilt
University Medical Center, Nashville, Tennessee 37232-2579, the
Research Center, Shriners Hospital for Children, Portland,
Oregon 97201, the ** Department of Pediatrics, Oregon
Health & Science University, Portland, Oregon 97201, and the
Department of Pediatrics, University of
Chieti, Chieti 66013, Italy
*
This work was supported in part by grant from the Medical
Research Foundation of Oregon (to A. S.). This work was presented in part at the 83rd Annual Meeting of the Endocrine
Society, Denver, June 2001 and the 6th Joint Meeting of the
Lawson-Wilkins Pediatric Endocrine Society and European Society
for Paediatric Endocrinology, Montreal, Canada, July 2001.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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