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- Title
Akt activation increases cellular cholesterol by promoting the proteasomal degradation of Niemann-Pick C1.
- Authors
Ximing Du; Yuxi Zhang; Sae Rom Jo; Xiaoyun Liu; Yanfei Qi; Brenna Osborne; Byrne, Frances L.; Smith, Greg C.; Turner, Nigel; Hoehn, Kyle L.; Brown, Andrew J.; Yang, Hongyuan
- Abstract
Null mutations of the Niemann-Pick type C1 (NPC1) gene cause NPC disease, a lysosomal storage disorder characterized by cholesterol accumulation in late endosomes (LE) and lysosomes (Ly).Nascent ormutated NPC1 is degraded through the ubiquitin- proteasome pathway, but how NPC1 degradation is regulated remains currently unknown. In the present study, we demonstrated a link between NPC1 degradation and the Akt (protein kinase B)/mTOR [mammalian (or mechanistic) target of rapamycin] signalling pathway in cervical cancer cell lines. We provided evidence that activated Akt/mTOR pathway increased NPC1 degradation by ~50% in C33A cells when compared with SiHa or HeLa cells. NPC1 degradation in C33A cells was reversed when Akt/mTOR activation was blocked by specific inhibitors or when mTORC1 (mTOR complex 1) was disrupted by regulatory associated protein of mTOR (Raptor) knockdown. Importantly, inhibition of the Akt/mTOR pathway led to decreased NPC1 ubiquitination in C33A cells, pointing to a role of Akt/mTOR in the proteasomal degradation of NPC1. Moreover, we found that NPC1 depletion in several cancer cell lines inhibited cell proliferation and migration. Our results uncover Akt as a key regulator of NPC1 degradation and link NPC1 to cancer cell proliferation and migration.
- Subjects
LYSOSOMAL storage diseases; ENDOSOMES; GENETIC mutation; PROTEIN kinase B; NIEMANN-Pick diseases; ETIOLOGY of diseases; PROTEASOMES
- Publication
Biochemical Journal, 2015, Vol 471, Issue 2, p243
- ISSN
0264-6021
- Publication type
Article
- DOI
10.1042/BJ20150602