HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53-dependent mitochondrial apoptosis

被引：25

作者：

Castelli, Marilena ^{[1
]}

Piobbico, Danilo ^{[1
]}

Chiacchiaretta, Martina ^{[1
]}

Brunacci, Cinzia ^{[1
]}

Pieroni, Stefania ^{[1
]}

Bartoli, Daniela ^{[1
]}

Gargaro, Marco ^{[1
]}

Fallarino, Francesca ^{[1
,2
]}

Puccetti, Paolo ^{[1
,2
]}

Soddu, Silvia ^{[3
]}

Della-Fazia, Maria Agnese ^{[1
]}

Servillo, Giuseppe ^{[1
,2
]}

机构：

[1] Univ Perugia, Dept Expt Med, Perugia, Italy

[2] Univ Perugia, Ctr Univ Ric Genom Funz CURGeF, Perugia, Italy

[3] IRCCS Regina Elena Natl Canc Inst, Unit Cellular Networks & Mol Therapeut Targets, Rome, Italy

来源：

EMBO REPORTS | 2020年 / 21卷 / 02期

关键词：

apoptosis; HOPS; mitochondria; p53; TMUB1; ubiquitin like; MUTANT P53; DNA-DAMAGE; TUMOR SUPPRESSION; CELL-DEATH; CANCER; PROTEIN; LIVER; HOPS; PROLIFERATION; STABILIZATION;

D O I：

10.15252/embr.201948073

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Apoptotic signalling by p53 occurs at both transcriptional and non-transcriptional levels, as p53 may act as a direct apoptogenic stimulus via activation of the intrinsic mitochondrial pathway. HOPS is a highly conserved, ubiquitously expressed shuttling protein with an ubiquitin-like domain. We generated Hops(-/-) mice and observed that they are viable with no apparent phenotypic defects. However, when treated with chemotherapeutic agents, Hops(-/-) mice display a significant reduction in apoptosis, suggesting an impaired ability to respond to genotoxic stressors. We show that HOPS acts as a regulator of cytoplasmic p53 levels and function. By binding p53, HOPS inhibits p53 proteasomal degradation and favours p53 recruitment to mitochondria and apoptosis induction. By interfering with importin alpha, HOPS further increases p53 cytoplasmic levels. Thus, HOPS promotes the p53-dependent mitochondrial apoptosis pathway by preserving cytoplasmic p53 from both degradation and nuclear uptake.

引用

页数：18

共 61 条

[51] A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas [J].