?Np63? down-regulates c-Myc modulator MM1 via E3 ligase HERC3 in the regulation of cell senescence.

ABSTRACT: p63 and c-Myc are key transcription factors controlling genes involved in the cell cycle and cellular senescence. We previously reported that p63? can destabilize MM1 protein to derepress c-Myc, resulting in cell cycle progress and tumorigenesis. However, how the proteasomal degradation of MM1 is facilitated remains unclear. In the present study, we identified a novel E3 ligase, HERC3, which can mediate ubiquitination of MM1 and promote its proteasome-dependent degradation. We found that ?Np63? transcriptionally up-regulates HERC3 and knockdown of HERC3 abrogates ?Np63?-induced down-regulation of MM1. Either overexpression of MM1 or ablation of HERC3 induces cell senescence, while knockdown of MM1 rescues cell senescence induced by deficiency of either ?Np63? or HERC3, implicating the involvement of the ?Np63?/HERC3/MM1/c-Myc axis in the modulation of cell senescence. Additionally, our Oncomine analysis indicates activation of the ?Np63?/HERC3/MM1/c-Myc axis in invasive breast carcinoma. Together, our data illuminate a novel axis regulating cell senescence: ?Np63? stimulates transcription of E3 ligase HERC3, which mediates ubiquitination of c-Myc modulator MM1 and targets it to proteasomal degradation; subsequently, c-Myc is derepressed by ?Np63?, thereby cell senescence is modulated by this axis. Our work provides a new interpretation of crosstalk between p63 and c-Myc, and also sheds new light on ?Np63?-controlled cell senescence and tumorigenesis.

SUBMITTER: Chen Y 

PROVIDER: S-EPMC6261956 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature