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FEBS Lett. 2016 Aug;590(15):2375-97. doi: 10.1002/1873-3468.12301. Epub 2016 Aug 6.

p62/SQSTM1-Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer.

Author information

1
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, USA.
2
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
3
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.

Abstract

p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses, and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.

KEYWORDS:

HCC; NASH; NF-κB; NRF2; autophagy; mTORC1; p62/SQSTM1

PMID:
27404485
PMCID:
PMC4983218
DOI:
10.1002/1873-3468.12301
[Indexed for MEDLINE]
Free PMC Article

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