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CAMK2γ Antagonizes mTORC1 Activation during Hepatocarcinogenesis
Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in hu...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408319/ https://www.ncbi.nlm.nih.gov/pubmed/27819676 http://dx.doi.org/10.1038/onc.2016.400 |
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author | Meng, Zhipeng Ma, Xiaoxiao Du, Juan Wang, Xiaoqiong He, Min Gu, Ying Zhang, Jiawei Han, Weidong Fang, Zhipeng Gan, Xiaoxian Van Ness, Carl Fu, Xianghui Schones, Dustin E Xu, Rongzhen Huang, Wendong |
author_facet | Meng, Zhipeng Ma, Xiaoxiao Du, Juan Wang, Xiaoqiong He, Min Gu, Ying Zhang, Jiawei Han, Weidong Fang, Zhipeng Gan, Xiaoxian Van Ness, Carl Fu, Xianghui Schones, Dustin E Xu, Rongzhen Huang, Wendong |
author_sort | Meng, Zhipeng |
collection | PubMed |
description | Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ(−/−) mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuats the compensatory proliferation of hepatocytes in CAMK2γ(−/−) livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis. |
format | Online Article Text |
id | pubmed-5408319 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
record_format | MEDLINE/PubMed |
spelling | pubmed-54083192017-10-27 CAMK2γ Antagonizes mTORC1 Activation during Hepatocarcinogenesis Meng, Zhipeng Ma, Xiaoxiao Du, Juan Wang, Xiaoqiong He, Min Gu, Ying Zhang, Jiawei Han, Weidong Fang, Zhipeng Gan, Xiaoxian Van Ness, Carl Fu, Xianghui Schones, Dustin E Xu, Rongzhen Huang, Wendong Oncogene Article Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ(−/−) mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuats the compensatory proliferation of hepatocytes in CAMK2γ(−/−) livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis. 2016-11-07 2017-04-27 /pmc/articles/PMC5408319/ /pubmed/27819676 http://dx.doi.org/10.1038/onc.2016.400 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Meng, Zhipeng Ma, Xiaoxiao Du, Juan Wang, Xiaoqiong He, Min Gu, Ying Zhang, Jiawei Han, Weidong Fang, Zhipeng Gan, Xiaoxian Van Ness, Carl Fu, Xianghui Schones, Dustin E Xu, Rongzhen Huang, Wendong CAMK2γ Antagonizes mTORC1 Activation during Hepatocarcinogenesis |
title | CAMK2γ Antagonizes mTORC1 Activation during Hepatocarcinogenesis |
title_full | CAMK2γ Antagonizes mTORC1 Activation during Hepatocarcinogenesis |
title_fullStr | CAMK2γ Antagonizes mTORC1 Activation during Hepatocarcinogenesis |
title_full_unstemmed | CAMK2γ Antagonizes mTORC1 Activation during Hepatocarcinogenesis |
title_short | CAMK2γ Antagonizes mTORC1 Activation during Hepatocarcinogenesis |
title_sort | camk2γ antagonizes mtorc1 activation during hepatocarcinogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408319/ https://www.ncbi.nlm.nih.gov/pubmed/27819676 http://dx.doi.org/10.1038/onc.2016.400 |
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