PKR-mediated degradation of STAT1 regulates osteoblast differentiation.
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.
Yoshida
Kaya
K
Department 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
Okamura
Hirohiko
H
Amorim
Bruna Rabelo
BR
Hinode
Daisuke
D
Yoshida
Hideo
H
Haneji
Tatsuji
T
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D060588:LIM Domain Proteins; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D054875:Ubiquitination; D019892:eIF-2 Kinase / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D015850:Interleukin-6; D060588:LIM Domain Proteins; C508508:Pdlim2 protein, mouse; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D044767:Ubiquitin-Protein Ligases; D019892:eIF-2 Kinase; D000469:Alkaline Phosphatase; D045726:Metalloproteases