Pin1 Associates with and Induces Translocation of CRTC2 to the Cytosol, Thereby Suppressing cAMP-responsive Element Transcriptional Activity
JBC_285_33018.pdf 4.87 MB
cAMP responsive element (CRE)
phosphoenolpyruvate carboxykinase (PEPCK)
Pin1 is a unique regulator, which catalyzes the conversion of a specific phospho-Ser/Thr-Pro-containing motif in target proteins. Herein, we identified CRTC2 as a Pin1-binding protein by overexpressing Pin1 with Myc and FLAG tags in mouse livers and subsequent purification of the complex containing Pin1. The association between Pin1 and CRTC2 was observed not only in overexpression experiments but also endogenously in the mouse liver. Interestingly, Ser(136) in the nuclear localization signal of CRTC2 was shown to be involved in the association with Pin1. Pin1 overexpression in HepG2 cells attenuated forskolin- induced nuclear localization of CRTC2 and cAMP-responsive element (CRE) transcriptional activity, whereas gene knockdown of Pin1 by siRNA enhanced both. Pin1 also associated with CRTC1, leading to their cytosol localization, essentially similar to the action of CRTC2. Furthermore, it was shown that CRTC2 associated with Pin1 did not bind to CREB. Taken together, these observations indicate the association of Pin1 with CRTC2 to decrease the nuclear CBP.CRTC.CREB complex. Indeed, adenoviral gene transfer of Pin1 into diabetic mice improved hyperglycemia in conjunction with normalizing phosphoenolpyruvate carboxykinase mRNA expression levels, which is regulated by CRE transcriptional activity. In conclusion, Pin1 regulates CRE transcriptional activity, by associating with CRTC1 or CRTC2.
The Journal of Biological Chemistry
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The American Society for Biochemistry and Molecular Biology, Inc.
Copyright (c) 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
This research was originally published in the Journal of Biological Chemistry; Yusuke Nakatsu, Hideyuki Sakoda, Akifumi Kushiyama, Hiraku Ono, Midori Fujishiro, Nanao Horike, Masayasu Yoneda, Haruya Ohno, Yoshihiro Tsuchiya, Hideaki Kamata, Hidetoshi Tahara, Toshiaki Isobe, Fusanori Nishimura, Hideki Katagiri, Yoshitomo Oka, Toshiaki Fukushima, Shin-Ichiro Takahashi, Hiroki Kurihara, Takafumi Uchida and Tomoichiro Asano; Pin1 Associates with and Induces Translocation of CRTC2 to the Cytosol, Thereby Suppressing cAMP-responsive Element Transcriptional Activity; J. Biol. Chem., 2010, 285, 33018-33027 © the American Society for Biochemistry and Molecular Biology.
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Graduate School of Biomedical Science