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Exp Cell Res. 2009 Jul 15;315(12):2105-14. doi: 10.1016/j.yexcr.2009.02.003. Epub 2009 Feb 20.

PKR-mediated degradation of STAT1 regulates osteoblast differentiation.

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  • 1Department of Fundamental Oral Health Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto, Tokushima 770-8504, Japan. kaya@dent.tokushima-u.ac.jp

Abstract

The double-stranded RNA-dependent protein kinase (PKR) plays a critical role in various biological responses including antiviral defense, cell differentiation, apoptosis, and tumorigenesis. In this study, we investigated whether PKR could affect the post-translational modifications of STAT1 protein and whether these modifications regulate osteoblast differentiation. We demonstrated that PKR was necessary for the ubiquitination of STAT1 protein. The expressions of bone-related genes such as type I collagen, integrin binding sialoprotein, osteopontin, and osterix were suppressed in osteoblasts lacking PKR activity. In contrast, the expressions of interleukin-6 and matrix metalloproteinases 8 and 13 increased in PKR-mutated osteoblasts. The expression and degradation of STAT1 protein were regulated by PKR in a SLIM-dependent pathway. Inhibition of SLIM by RNA interference resulted in the decreased activity of Runx2 in osteoblasts. Stimulation of interleukin-6 expression and suppression of alkaline phosphatase activity were regulated through by SLIM-dependent pathway. However, expressions of bone-related genes and MMPs were regulated by SLIM-independent pathway. Our present results suggest that the aberrant accumulation of STAT1 protein induced by loss of PKR regulate osteoblast differentiation through both SLIM/STAT1-dependent and -independent pathways.

PMID:
19230833
[PubMed - indexed for MEDLINE]
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