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Thioredoxin-interacting Protein Promotes Islet Amyloid Polypeptide Expression through miR-124a and FoxA2.

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Title: Thioredoxin-interacting Protein Promotes Islet Amyloid Polypeptide Expression through miR-124a and FoxA2.
Authors: Gu Jing1, Westwell-Roper, Clara2, Junqin Chen1, Guanlan Xu1, Verchere, C. Bruce2, Shalev, Anath1
Source: Journal of Biological Chemistry. 4/25/2014, Vol. 289 Issue 17, p11807-11815. 9p.
Subjects: Thioredoxin-interacting protein, Polypeptides, Chemical synthesis, Apoptosis, Pancreatic beta cells, Immunoprecipitation, Transcription factors, Chromatin
Abstract: Thioredoxin-interacting protein (TXNIP) is up-regulated by glucose and diabetes and plays a critical role in glucotoxicity, inflammation, and beta-cell apoptosis, whereas we have found that TXNIP deficiency protects against diabetes. Interestingly, human islet amyloid polypeptide (IAPP) is also induced by glucose, aggregates into insoluble amyloid fibrils found in islets of most individuals with type 2 diabetes and promotes inflammation and beta-cell cytotoxicity. However, so far no connection between TXNIP and IAPP signaling had been reported. Using TXNIP gain and loss of function experiments, INS-1 beta-cells and beta-cell-specific Txnip knock-out mice, we now found that TXNIP regulates IAPP expression. Promoter analyses and chromatin- immunoprecipitation assays further demonstrated that TXNIP increases IAPP expression at the transcriptional level, and we discovered that TXNIP-induced FoxA2 (forkhead box A2) transcription factor expression was conferring this effect by promoting FoxA2 enrichment at the proximal FoxA2 site in the IAPP promoter. Moreover, we found that TXNIP down-regulates miR-124a expression, a microRNA known to directly target FoxA2. Indeed, miR-124a overexpression led to decreased FoxA2 expression and IAPP promoter occupancy and to a significant reduction in IAPP mRNA and protein expression and also effectively inhibited TXNIP-induced IAPP expression. Thus, our studies have identified a novel TXNIP/miR-124a/ FoxA2/IAPP signaling cascade linking the critical beta-cell signaling pathways of TXNIP and IAPP and thereby provide new mechanistic insight into an important aspect of transcriptional regulation and beta-cell biology. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
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  Data: Thioredoxin-interacting Protein Promotes Islet Amyloid Polypeptide Expression through miR-124a and FoxA2.
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  Data: <searchLink fieldCode="AR" term="%22Gu+Jing%22">Gu Jing</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Westwell-Roper%2C+Clara%22">Westwell-Roper, Clara</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Junqin+Chen%22">Junqin Chen</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Guanlan+Xu%22">Guanlan Xu</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Verchere%2C+C%2E+Bruce%22">Verchere, C. Bruce</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Shalev%2C+Anath%22">Shalev, Anath</searchLink><relatesTo>1</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 4/25/2014, Vol. 289 Issue 17, p11807-11815. 9p.
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  Data: <searchLink fieldCode="DE" term="%22Thioredoxin-interacting+protein%22">Thioredoxin-interacting protein</searchLink><br /><searchLink fieldCode="DE" term="%22Polypeptides%22">Polypeptides</searchLink><br /><searchLink fieldCode="DE" term="%22Chemical+synthesis%22">Chemical synthesis</searchLink><br /><searchLink fieldCode="DE" term="%22Apoptosis%22">Apoptosis</searchLink><br /><searchLink fieldCode="DE" term="%22Pancreatic+beta+cells%22">Pancreatic beta cells</searchLink><br /><searchLink fieldCode="DE" term="%22Immunoprecipitation%22">Immunoprecipitation</searchLink><br /><searchLink fieldCode="DE" term="%22Transcription+factors%22">Transcription factors</searchLink><br /><searchLink fieldCode="DE" term="%22Chromatin%22">Chromatin</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Thioredoxin-interacting protein (TXNIP) is up-regulated by glucose and diabetes and plays a critical role in glucotoxicity, inflammation, and beta-cell apoptosis, whereas we have found that TXNIP deficiency protects against diabetes. Interestingly, human islet amyloid polypeptide (IAPP) is also induced by glucose, aggregates into insoluble amyloid fibrils found in islets of most individuals with type 2 diabetes and promotes inflammation and beta-cell cytotoxicity. However, so far no connection between TXNIP and IAPP signaling had been reported. Using TXNIP gain and loss of function experiments, INS-1 beta-cells and beta-cell-specific Txnip knock-out mice, we now found that TXNIP regulates IAPP expression. Promoter analyses and chromatin- immunoprecipitation assays further demonstrated that TXNIP increases IAPP expression at the transcriptional level, and we discovered that TXNIP-induced FoxA2 (forkhead box A2) transcription factor expression was conferring this effect by promoting FoxA2 enrichment at the proximal FoxA2 site in the IAPP promoter. Moreover, we found that TXNIP down-regulates miR-124a expression, a microRNA known to directly target FoxA2. Indeed, miR-124a overexpression led to decreased FoxA2 expression and IAPP promoter occupancy and to a significant reduction in IAPP mRNA and protein expression and also effectively inhibited TXNIP-induced IAPP expression. Thus, our studies have identified a novel TXNIP/miR-124a/ FoxA2/IAPP signaling cascade linking the critical beta-cell signaling pathways of TXNIP and IAPP and thereby provide new mechanistic insight into an important aspect of transcriptional regulation and beta-cell biology. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1074/jbc.M113.525022
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      – Code: eng
        Text: English
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        PageCount: 9
        StartPage: 11807
    Subjects:
      – SubjectFull: Thioredoxin-interacting protein
        Type: general
      – SubjectFull: Polypeptides
        Type: general
      – SubjectFull: Chemical synthesis
        Type: general
      – SubjectFull: Apoptosis
        Type: general
      – SubjectFull: Pancreatic beta cells
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      – SubjectFull: Immunoprecipitation
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      – SubjectFull: Transcription factors
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      – SubjectFull: Chromatin
        Type: general
    Titles:
      – TitleFull: Thioredoxin-interacting Protein Promotes Islet Amyloid Polypeptide Expression through miR-124a and FoxA2.
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            NameFull: Gu Jing
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            NameFull: Guanlan Xu
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              M: 04
              Text: 4/25/2014
              Type: published
              Y: 2014
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              Value: 289
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