Dataset Information

Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXR?.

ABSTRACT: Retinoid X receptor-alpha (RXR?) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXR? (tRXR?), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85? subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXR? tetramers via a 'three-pronged' combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXR?, owing to the head-tail interaction that is absent in tRXR?. We also identify an LxxLL motif in p85?, which binds to the coactivator-binding groove on tRXR? and dissociates from tRXR? upon tRXR? tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXR? and provide molecular insights into the development of RXR? cancer therapeutics.

SUBMITTER: Chen L

PROVIDER: S-EPMC5520057 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRα.

Chen Liqun L Aleshin Alexander E AE Alitongbieke Gulimiran G Zhou Yuqi Y Zhang Xindao X Ye Xiaohong X Hu Mengjie M Ren Gaoang G Chen Ziwen Z Ma Yue Y Zhang Duo D Liu Shuai S Gao Weiwei W Cai Lijun L Wu Lingjuan L Zeng Zhiping Z Jiang Fuquan F Liu Jie J Zhou Hu H Cadwell Gregory G Liddington Robert C RC Su Ying Y Zhang Xiao-Kun XK

Nature communications 20170717

Retinoid X receptor-alpha (RXRα) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRα (tRXRα), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85α subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and s ...[more]

PMID: 28714476

Similar Datasets

Project description:BackgroundIncreasing evidence has proven that the γ-secretase complex plays significant roles in the carcinogenesis of malignancies. However, the independent effect of nicastrin (NCSTN), the largest constituent of the γ-secretase complex, on the progression of hepatocellular carcinoma (HCC) remains to be discovered.MethodsIn our study, we used open online databases, including the Oncomine database, GEPIA and KMPlotter, to analyse the expression of 4 genes and their correlation with prognosis in HCC. NCSTN expression in 60 HCC patients from our centre was determined by immunohistochemical staining and qRT-PCR. The clinical and prognostic significance of NCSTN expression were analysed statistically. Stable Sk-hep1 cell lines with NCSTN overexpression were established using lentivirus-based vectors, and RNAi technology was used to transiently downregulate NCSTN expression in HepG2 cell lines. Cell growth and apoptosis were assessed by using EdU, clone formation, flow cytometry and Western blotting assays.ResultsBioinformatics analysis showed that NCSTN mRNA expression was generally higher in HCC tissues than in normal tissues according to a meta-analysis of 9 HCC datasets, excluding PS-1, PEN-2 and APH-1. Moreover, NCSTN was associated with a poor prognosis in HCC patients from The Cancer Genome Atlas (TCGA). Although the relationship between NCSTN levels and the clinicopathological features of HCC patients was not significant, a survival analysis of HCC patients from TCGA indicated that overall and disease-free survival were significantly associated with NCSTN expression. NCSTN expression in HCC cell lines regulated cell growth and apoptosis in vitro. NCSTN downregulation in HepG2 cells inhibited tumour growth ability in vivo. In addition, NCSTN downregulation in HepG2 cell lines decreased p-PI3K and p-Akt expression, and IGF1, a PI3K/Akt activator, neutralized the effects on PI3K and Akt phosphorylation. Moreover, NCSTN overexpression in Sk-hep1 cells activated the PI3K/Akt signalling pathway, and MK-2206, a PI3K/Akt inhibitor, reversed this activation according to Western blotting analysis.ConclusionsWe suggest that NCSTN serves as an oncogene in HCC by promoting growth and inhibiting apoptosis via the PI3K/Akt pathway, providing a potential novel therapeutic target for HCC treatment.

Dataset Information

Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXR?.

Publications

Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRα.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets