Conflict of interest: We confirm that all authors fulfil all conditions required for authorship. We also confirm that there is no potential conflict of interest or financial dependence regarding this publication.
The prolyl isomerase Pin1 interacts with and downregulates the activity of AMPK leading to induction of tumorigenicity of hepatocarcinoma cells
Article first published online: 30 APR 2012
© 2012 Wiley Periodicals, Inc.
Volume 52, Issue 10, pages 813–823, October 2013
How to Cite
Khanal, P., Kim, G., Yun, H. J., Cho, H.-G. and Choi, H. S. (2013), The prolyl isomerase Pin1 interacts with and downregulates the activity of AMPK leading to induction of tumorigenicity of hepatocarcinoma cells. Mol. Carcinog., 52: 813–823. doi: 10.1002/mc.21920
- Issue published online: 19 SEP 2013
- Article first published online: 30 APR 2012
- Manuscript Accepted: 6 APR 2012
- Manuscript Revised: 23 MAR 2012
- Manuscript Received: 29 NOV 2011
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Education, Science, and Technology. Grant Numbers: 2009-0073468, 2011-0009728
- cell transformation
Pin1 is a unique regulator that catalyzes the conversion of a specific phospho-Ser/Thr-Pro-containing motif in target proteins. Herein, we identified AMP-activated protein kinase (AMPK) as a Pin1-binding protein. Pin1 wild-type, but not Pin1 mutant at serine 16 (S16A), associated with AMPK. Reciprocally, the constitutively active form of AMPK (AMPK-CA), but not the dominant negative form of AMPK (AMPK-DN), interacted with Pin1 wild type. In addition, mutation of Ser176 site in AMPK led to a significant loss of binding between AMPK and Pin1. Ablation of the Pin1 gene in MEFs enhanced AMPK phosphorylation induced by AICAR. Pin1 overexpression in Pin1−/− MEFs and SK-HEP-1 cells attenuated AMPK phosphorylation induced by EGF, whereas gene knockdown of Pin1 by siRNA enhanced it. The association between Pin1 and AMPK was increased by EGF, leading to their interaction with protein phosphatase-2A (PP2A). Furthermore, Pin1 increased the PP2A activity induced by EGF. In addition, AMPK-WT and AMPK-CA, but not AMPK-DN, inhibited EGF-induced neoplastic cell transformation of JB6 Cl41 cells and tumorigenicity of SK-HEP-1 cells. The overexpression of Pin1 in JB6 Cl41 cells and SK-HEP-1 cells attenuated the inhibitory effect of AMPK in EGF-induced neoplastic cell transformation of JB6 Cl41 and tumorigenicity of SK-HEP-1 cells, respectively. Taken together, these results indicate that Pin1 plays a pivotal role in EGF-induced carcinogenesis through downregulation of AMPK activity in hepatocarcinoma cells. © 2012 Wiley Periodicals, Inc.