Anks4b, a Novel Target of HNF4α Protein, Interacts with GRP78 Protein and Regulates Endoplasmic Reticulum Stress-induced Apoptosis in Pancreatic β-Cells

Sato, Yuzo; Hatta, Mitsutoki; Karim, Md. Fazlul; Sawa, Tomohiro; Wei, Fan Yan; Sato, Shuichi; Magnuson, Mark A.; Gonzalez, Frank J.; Tomizawa, Kazuhito; Akaike, Takaaki; Yoshizawa, Tatsuya; Yamagata, Kazuya

doi:10.1074/jbc.m112.368779

Cited by 33 publications

(31 citation statements)

References 42 publications

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“…Thus, though the results of the previous screens have not been validated and the direct relationship between HNF4␣ and XBP1 has apparently never been specifically studied prior to the current work, our results are not entirely unprecedented. Indeed, HNF4␣ has also been shown to regulate expression of ankyrin repeat and sterile ␣ motif domain containing 4b (Anks4b), a protein that binds ER chaperones and augments the ER stress response, supporting our hypothesis that HNF4␣ is required for the establishment and maintenance of the ER in ␤-cells (42).…”

Section: Discussionsupporting

confidence: 51%

Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4Α) Is Vital to Beta-cell Function

Moore

Jin

et al. 2016

Journal of Biological Chemistry

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The transcription factor, X-box-binding protein-1 (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4␣ (HNF4␣) directly induces XBP1 expression. Mutations in HNF4␣ cause Mature-Onset Diabetes of the Young I (MODYI), a subset of diabetes characterized by diminished GSIS. In mouse models, cell lines, and ex vivo islets, using dominant negative and human-disease-allele point mutants or knock-out and knockdown models, we show that disruption of HNF4␣ caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca 2؉ signaling; we show that diminished XBP1 and/or HNF4␣ in ␤-cells led to impaired ER Ca 2؉ homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4␣-deficient ␤-cells. Our findings uncover a transcriptional relationship between HNF4␣ and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion.Cells use transcription factors to regulate expression of gene cohorts that coordinate response to stress, determine specific developmental fates, and scale intracellular architecture during development and disease(1, 2). When the biosynthetic load of a cell is increased and misfolded proteins accumulate in the endoplasmic reticulum (ER), 2 the volume and composition of the ER is altered to facilitate the synthesis and processing of nascent polypeptides via the unfolded protein response (UPR) pathway. One of the principal components of the UPR is the transcription factor X-box-binding protein 1 (XBP1), which is canonically activated via IRE1 splicing of the XBP1 transcript during ER stress (3, 4). However, XBP1 also establishes and maintains the subcellular machinery for synthesizing large quantities of protein during the normal development of professional secretory cells (2, 5). While the majority of genes activated by XBP1 are involved in ER biogenesis, up to 40% of its targets are not directly linked to the ER-stress response (6), further supporting its functions outside the UPR. In addition, the increased XBP1 that coordinates the scaling up of the secretory apparatus during development and homeostasis of dedicated secretory cells does not seem to require activation of the UPR (7). How XBP1 is induced and maintained during differentiation of secretory cells even in the absence of substantial ER stress is unclear, but a potential alternative mechanism is that Xbp1 may also be transcriptionally regulated. Hepatocyte Nuclear Factor 4-alpha (HNF4␣) is a highly conserved transcription factor responsible for orchestrating the early development and maintenance of multiple adult organs. As a master developmental regulator, HNF4␣ likely acts upstream of the factors that establish the extensive cellular machinery required in professional secretory cell lineages within those organs. Despite overlapping expression and function, no direct relationship between HNF4␣ and Xbp1 h...

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Section: Discussionsupporting

confidence: 51%

Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4Α) Is Vital to Beta-cell Function

Moore

Jin

et al. 2016

Journal of Biological Chemistry

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“…5B). Previous work by our lab and others has defined HNF4␣ as a crucial regulator of multiple factors required for the development and maintenance of vast ER networks that secretory cells require to synthesize and secrete large biosynthetic loads (41,47). To determine if HNF4␣ is required to maintain the ER in the gastric epithelium, we examined the effect of loss of HNF4␣ by immunofluorescent staining for the ER-localized protein, Calregulin.…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte nuclear factor 4α is required for cell differentiation and homeostasis in the adult mouse gastric epithelium

Moore

Khurana

Huh

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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We have previously shown that the sequential transcription factors Xbp1→Mist1 (Bhlha15) govern the ultrastructural maturation of the secretory apparatus in enzyme-secreting zymogenic chief cells (ZCs) in the gastric unit. Here we sought to identify transcriptional regulators upstream of X-box binding protein 1 (XBP1) and MIST1. We used immunohistochemistry to characterize Hnf4α(flox/flox) adult mouse stomachs after tamoxifen-induced deletion of Hnf4α We used qRT-PCR, Western blotting, and chromatin immunoprecipitation to define the molecular interaction between hepatocyte nuclear factor 4 alpha (HNF4α) and Xbp1 in mouse stomach and human gastric cells. We show that HNF4α protein is expressed in pit (foveolar) cells, mucous neck cells, and zymogenic chief cells (ZCs) of the corpus gastric unit. Loss of HNF4α in adult mouse stomach led to reduced ZC size and ER content, phenocopying previously characterized effects of Xbp1 deletion. However, HNF4α(Δ/Δ) stomachs also exhibited additional phenotypes including increased proliferation in the isthmal stem cell zone and altered mucous neck cell migration, indicating a role of HNF4α in progenitor cells as well as in ZCs. HNF4α directly occupies the Xbp1 promoter locus in mouse stomach, and forced HNF4α expression increased abundance of XBP1 mRNA in human gastric cancer cells. Finally, as expected, loss of HNF4α caused decreased Xbp1 and Mist1 expression in mouse stomachs. We show that HNF4α regulates homeostatic proliferation in the gastric epithelium and is both necessary and sufficient for the upstream regulation of the Xbp1→Mist1 axis in maintenance of ZC secretory architecture.

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“…BiP is an ER-localized HSP70-class chaperone which senses and binds to the misfolded or unfolded ER proteins and initiates ER stress response (Hammadi et al 2013;Mozos et al 2011;Sato et al 2012). Activation of the transducer then leads to the PERK activation (Szegezdi et al 2006) and to p-eIF2α, which inhibits the synthesis of such proteins as anti-apoptosis molecules (Harding et al 1999;Shi et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Is Involved in the Lidocaine-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells

Han

2014

J Mol Neurosci

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Lidocaine has been indicated to promote apoptosis and to promote endoplasmic reticulum (ER) stress. However, the mechanism underlining ER stress-mediated apoptosis is unclear. In the present study, we investigated the promotion to ER stress in the lidocaine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Firstly, we confirmed that lidocaine treatment induced apoptosis in SH-SY5Y cells, time-dependently and dose-dependently, via MTT cell viability assay and annexin V/FITC apoptosis detection with a FACScan flow cytometer. And the anti-apoptosis Bcl-2 and Bcl-xL were downregulated, whereas the apoptosis-executive caspase 3 was promoted through Western blot assay and caspase 3 activity assay. Moreover, the ER stress-associated binding immunoglobulin protein (BiP), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP) were also upregulated at both mRNA and protein levels by lidocaine treatment. On the other hand, downregulation of the ER stress-associated BiP by RNAi method not only blocked the lidocaine-promoted ER stress but also attenuated the lidocaine-induced SH-SY5Y cell apoptosis. In conclusion, the present study confirmed the involvement of ER stress in the lidocaine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Our study provides a better understanding on the mechanism of lidocaine's neurovirulence.

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Anks4b, a Novel Target of HNF4α Protein, Interacts with GRP78 Protein and Regulates Endoplasmic Reticulum Stress-induced Apoptosis in Pancreatic β-Cells

Cited by 33 publications

References 42 publications

Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4Α) Is Vital to Beta-cell Function

Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4Α) Is Vital to Beta-cell Function

Hepatocyte nuclear factor 4α is required for cell differentiation and homeostasis in the adult mouse gastric epithelium

Endoplasmic Reticulum Stress Is Involved in the Lidocaine-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells

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