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. Author manuscript; available in PMC: 2017 Jun 13.
Published in final edited form as: Cancer Cell. 2016 May 19;29(6):935–948. doi: 10.1016/j.ccell.2016.04.006

Figure 7. p62 expression and signaling during HCC development.

Figure 7

p62 gene transcription is induced by NRF2 and NF-κB, which are activated by oxidative stress and inflammation, respectively. Newly synthesized p62 protein binds ubiquitinated proteins and organelles and LC3 on phagophore membranes to promote autophagy and lysosomal degradation. mTORC1 activation and ER stress promote p62 accumulation by interfering with initiation of autophagy, whereas alcohol and HCV affect p62 by interfering with termination of autophagy and can also lead to IKK/NF-κB activation. Once p62 accumulates it leads to IKK/NF-κB activation via TRAF6 binding and NRF2 activation through titration of Keap1. p62 accumulation also activates mTORC1/c-Myc signaling to alter metabolism and promote proliferation. mTORC1-mediated p62 phosphorylation enhances NRF2 activation.