STAT1

Identification of STAT-1 as a molecular target of IGFBP-3 in the process of chondrogenesis.

"Using the RCJ3.1C5.18 chondrogenic cells, which in culture progresses from undifferentiated to terminally differentiated chondrocytes, we have shown 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. STAT-1 is a major intracellular signaling and transcriptional target of the IGF-independent apoptotic effect of IGFBP-3 in chondrogenesis."

"IGFBP-3 binds to the extracellular matrix and to cell membrane receptors and is transported in the nucleus by the importin β subunit, where it binds to the retinoid X receptor-α "

"IGFBP-3 induced apoptosis in chondroprogenitors."

"In chondrocytes, STAT-1 has been implicated as a key signaling molecule that mediates the antiproliferative and apoptotic activity of FGFR-3"