These authors contributed equally to this work.
Article first published online: 7 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 1, pages 140–151, January 2013
How to Cite
Guo, Y., Wang, W., Wang, J., Feng, J., Wang, Q., Jin, J., Lv, M., Li, X., Li, Y., Ma, Y., Shen, B. and Zhang, J. (2013), Receptor for activated C kinase 1 promotes hepatocellular carcinoma growth by enhancing mitogen-activated protein kinase kinase 7 activity. Hepatology, 57: 140–151. doi: 10.1002/hep.25978
Potential conflict of interest: Nothing to report.
This work was supported by grants from the National Natural Science Foundation of China (grant nos. 30973547 and 31100544), the Key Natural Science Program of Beijing (grant no.: 7101008), and the National Key Basic Research Program of China (grant no.: 2010CB911904).
- Issue published online: 7 JAN 2013
- Article first published online: 7 JAN 2013
- Accepted manuscript online: 17 AUG 2012 03:29PM EST
- Manuscript Accepted: 13 JUL 2012
- Manuscript Received: 7 JAN 2012
c-Jun N-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) superfamily. The activation of JNK is mediated by sequential protein phosphorylation through a MAPK module, namely, MAPK kinase kinase (MAP3K or MEKK) MAPK kinase (MAP2K or MKK) MAPK. Elevated levels of JNK activity have been frequently observed in hepatocellular carcinoma (HCC) and have been demonstrated to contribute to HCC growth by promoting HCC cell proliferation and resistance to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)- or Fas-mediated apoptosis. Chronic inflammation contributes to the up-regulation of JNK activity in HCC. However, it remains unknown whether aberrant JNK activity also results from some cell intrinsic defect(s). Here, we show that receptor for activated C kinase 1 (RACK1), an adaptor protein implicated in the regulation of multiple signaling pathways, could engage in a direct interaction with MKK7, the JNK-specific MAP2K, in human HCC cells. Levels of RACK1 protein show correlation with the activity of the JNK pathway in human HCC tissues and cell lines. RACK1 loss-of-function or gain-of-function analyses indicate that RACK1 enhances MKK7/JNK activity in human HCC cells. Further exploration reveals that the interaction of RACK1 with MKK7 is required for the enhancement of MKK7/JNK activity by RACK1. RACK1/MKK7 interaction facilitates the association of MKK7 with MAP3Ks, thereby enhancing MKK7 activity and promoting in vitro HCC cell proliferation and resistance to TRAIL- or Fas-mediated apoptosis as well as in vivo tumor growth. Conclusion: Overexpressed RACK1 augments JNK activity and thereby promotes HCC growth through directly binding to MKK7 and enhancing MKK7 activity. (HEPATOLOGY 2013)