TY - JOUR
T1 - PKR-mediated degradation of STAT1 regulates osteoblast differentiation
AU - Yoshida, Kaya
AU - Okamura, Hirohiko
AU - Amorim, Bruna Rabelo
AU - Hinode, Daisuke
AU - Yoshida, Hideo
AU - Haneji, Tatsuji
PY - 2009/7/15
Y1 - 2009/7/15
N2 - 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.
AB - 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.
KW - Differentiation
KW - Osteoblast
KW - PKR
KW - SLIM
KW - STAT1
UR - http://www.scopus.com/inward/record.url?scp=67349116079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349116079&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2009.02.003
DO - 10.1016/j.yexcr.2009.02.003
M3 - Article
C2 - 19230833
AN - SCOPUS:67349116079
SN - 0014-4827
VL - 315
SP - 2105
EP - 2114
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 12
ER -