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NF-?B signaling is required for XBP1 (unspliced and spliced)-mediated effects on antiestrogen responsiveness and cell fate decisions in breast cancer.

ABSTRACT: Antiestrogen therapy induces the unfolded protein response (UPR) in estrogen receptor-positive (ER(+)) breast cancer. X-box binding protein 1 (XBP1), which exists in the transcriptionally inactive unspliced form [XBP1(U)] and the spliced active form [XBP1(S)], is a key UPR component mediating antiestrogen resistance. We now show a direct link between the XBP1 and NF-?B survival pathways in driving the cell fate decisions in response to antiestrogens in ER(+) breast cancer cells, both in vitro and in a xenograft mouse model. Using novel spliced and nonspliceable forms of XBP1, we show that XBP1(U) functions beyond being a dominant negative of XBP1(S). Both isoforms regulate NF-?B activity via ER?; XBP1(S) is more potent because it also directly regulates p65/RelA expression. These findings provide new insights into the fundamental signaling activities of spliced and unspliced XBP1 in breast cancer, establish NF-?B to be a mediator of these activities, and identify XBP1 and its splicing to be novel therapeutic targets.

SUBMITTER: Hu R

PROVIDER: S-EPMC4272419 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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NF-κB signaling is required for XBP1 (unspliced and spliced)-mediated effects on antiestrogen responsiveness and cell fate decisions in breast cancer.

Hu Rong R Warri Anni A Jin Lu L Zwart Alan A Riggins Rebecca B RB Fang Hong-Bin HB Clarke Robert R

Molecular and cellular biology 20141103 2

Antiestrogen therapy induces the unfolded protein response (UPR) in estrogen receptor-positive (ER(+)) breast cancer. X-box binding protein 1 (XBP1), which exists in the transcriptionally inactive unspliced form [XBP1(U)] and the spliced active form [XBP1(S)], is a key UPR component mediating antiestrogen resistance. We now show a direct link between the XBP1 and NF-κB survival pathways in driving the cell fate decisions in response to antiestrogens in ER(+) breast cancer cells, both in vitro an ...[more]

PMID: 25368386

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Project description:BACKGROUND AND AIM: We previously established that endoplasmic reticulum stress leads to unfolded protein response (UPR) that promotes liver fibrosis by activating hepatic stellate cell (HSC). We aimed to determine the role of X-box binding protein 1 (XBP1), one of three UPR effector pathways, in the fibrogenic HSC activation. METHODS: XBP1 expression was measured by qPCR in tunicamycin-treated human HSC lines (TWNT4 and LX2) and culture-activated human primary HSCs. XBP1 was overexpressed in primary human HSCs and the HSC lines, and fibrogenic genes (COL1A1, ACTA2, PDGFRB, MMP2, TIMP1) and encoded proteins were assessed by qPCR and Western blotting, respectively. Autophagy was inhibited by knockdown of ATG7. Genome-wide transcriptome profiling was performed to determine modulated molecular pathway by XBP1. In vivo XBP1 activation was assessed in transcriptome datasets of fibrotic mouse models and immunohistochemistry of human liver tissues. RESULTS: XBP1 overexpression accompanied both tunicamycin- and culture-based HSC activation. Ectopic overexpression of XBP1 induced fibrogenic gene expression in the HSC lines, which was inhibited by knockdown of ATG7. UPR pathway together with PDGFRB pathway, a hallmark of HSC activation, were induced in transcriptome profiles of XBP1-transduced HSC lines. Some known fibrogenic pathways such as transforming growth factor (TGF)-beta pathway were not induced, suggesting partial contribution of XBP1 to the entire fibrogenic HSC activation machinery. XBP1 target gene signature defined in our XBP1-overexpressing HSC lines was significantly induced in liver tissue transcriptome profiles of carbon tetrachloride-treated or bile duct-ligated mouse models, and XBP1 and alpha-smooth muscle actin (encoded by ACTA2, another hallmark of HSC activation) were co-localized in human fibrotic liver tissues, collectively supporting involvement of XBP1 in HSC activation and fibrogesis in vivo. CONCLUSIONS: XBP1-mediated UPR is at least partially responsible for fibrogenic HSC activation via autophagy.

Project description:Intron-containing mRNAs are subject to restricted nuclear export in higher eukaryotes. Retroviral replication requires the nucleocytoplasmic transport of both spliced and unspliced RNA transcripts, and RNA export mechanisms of gammaretroviruses are poorly characterized. Here, we report the involvement of the nuclear export receptor NXF1/TAP in the nuclear export of gammaretroviral RNA transcripts. We identified a conserved cis-acting element in the pol gene of gammaretroviruses, including murine leukemia virus (MLV) and xenotropic murine leukemia virus (XMRV), named the CAE (cytoplasmic accumulation element). The CAE enhanced the cytoplasmic accumulation of viral RNA transcripts and the expression of viral proteins without significantly affecting the stability, splicing, or translation efficiency of the transcripts. Insertion of the CAE sequence also facilitated Rev-independent HIV Gag expression. We found that the CAE sequence interacted with NXF1, whereas disruption of NXF1 ablated CAE function. Thus, the CAE sequence mediates the cytoplasmic accumulation of gammaretroviral transcripts in an NXF1-dependent manner. Disruption of NXF1 expression impaired cytoplasmic accumulations of both spliced and unspliced RNA transcripts of XMRV and MLV, resulting in their nuclear retention or degradation. Thus, our results demonstrate that gammaretroviruses use NXF1 for the cytoplasmic accumulation of both spliced and nonspliced viral RNA transcripts.Murine leukemia virus (MLV) has been studied as one of the classic models of retrovirology. Although unspliced host messenger RNAs are rarely exported from the nucleus, MLV actively exports unspliced viral RNAs to the cytoplasm. Despite extensive studies, how MLV achieves this difficult task has remained a mystery. Here, we have studied the RNA export mechanism of MLV and found that (i) the genome contains a sequence which supports the efficient nuclear export of viral RNAs, (ii) the cellular factor NXF1 is involved in the nuclear export of both spliced and unspliced viral RNAs, and, finally, (iii) depletion of NXF1 results in nuclear retention or degradation of viral RNAs. Our study provides a novel insight into MLV nuclear export.

Dataset Information

NF-?B signaling is required for XBP1 (unspliced and spliced)-mediated effects on antiestrogen responsiveness and cell fate decisions in breast cancer.

Publications

NF-κB signaling is required for XBP1 (unspliced and spliced)-mediated effects on antiestrogen responsiveness and cell fate decisions in breast cancer.

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