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Integrator of stress responses calmodulin binding transcription activator 1 (Camta1) Regulates miR-212/miR-132 Expression and insulin secretion

Mollet, Inês Guerra Uerra LU ; Malm, Helena Anna LU ; Wendt, Anna LU ; Orho-Melander, Marju LU and Eliasson, Lena LU (2016) In Journal of Biological Chemistry 291(35). p.18440-18452
Abstract

Altered microRNA profiles have been demonstrated in experimental models of type 2 diabetes, including in islets of the diabetic Goto-Kakizaki (GK) rat. Our bioinformatic analysis of conserved sequences in promoters of microRNAs, previously observed to be up-regulated in GK rat islets, revealed putative CGCG-core motifs on the promoter of the miR-212/miR-132 cluster, overexpression of which has been shown to increase insulin secretion. These motifs are possible targets of calmodulin binding transcription activators Camta1 and Camta2 that have been recognized as integrators of stress responses. We also identified putative NKE elements, possible targets of NK2 homeobox proteins like the essential islet transcription factor Nkx2-2. As... (More)

Altered microRNA profiles have been demonstrated in experimental models of type 2 diabetes, including in islets of the diabetic Goto-Kakizaki (GK) rat. Our bioinformatic analysis of conserved sequences in promoters of microRNAs, previously observed to be up-regulated in GK rat islets, revealed putative CGCG-core motifs on the promoter of the miR-212/miR-132 cluster, overexpression of which has been shown to increase insulin secretion. These motifs are possible targets of calmodulin binding transcription activators Camta1 and Camta2 that have been recognized as integrators of stress responses. We also identified putative NKE elements, possible targets of NK2 homeobox proteins like the essential islet transcription factor Nkx2-2. As Camtas can function as co-activators with NK2 proteins in other tissues, we explored the role of Camta1, Camta2, and Nkx2-2 in the regulation of the miR-212/miR-132 cluster and insulin secretion. We demonstrate that exposure of control Wistar or GK rat islets to 16.7 mM glucose increases miR-212/miR-132 expression but significantly less so in the GK rat. In addition, Camta1, Camta2, and Nkx2-2 were down-regulated in GK rat islets, and knockdown of Camta1 reduced miR-212/miR-132 promoter activity and miR-212/miR-132 expression, even under cAMP elevation. Knockdown of Camta1 decreased insulin secretion in INS-1 832/13 cells and Wistar rat islets but increased insulin content. Furthermore, knockdown of Camta1 reduced K+-induced insulin secretion and voltage-dependent Ca2+ currents. We also demonstrate Camta1 and Nkx2-2 protein interaction. These results indicate that Camta1 is required not only for expression of the miR-212/miR-132 cluster but at multiple levels for regulating beta cell insulin content and secretion.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Insulin, calmodulin binding, bioinformatics, rat
in
Journal of Biological Chemistry
volume
291
issue
35
pages
13 pages
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • Scopus:84984706989
ISSN
0021-9258
DOI
10.1074/jbc.M116.716860
language
English
LU publication?
yes
id
f070ffe9-9e77-4c99-bc1f-98b337fe48fd
date added to LUP
2016-09-21 10:59:38
date last changed
2016-09-22 03:00:05
@misc{f070ffe9-9e77-4c99-bc1f-98b337fe48fd,
  abstract     = {<p>Altered microRNA profiles have been demonstrated in experimental models of type 2 diabetes, including in islets of the diabetic Goto-Kakizaki (GK) rat. Our bioinformatic analysis of conserved sequences in promoters of microRNAs, previously observed to be up-regulated in GK rat islets, revealed putative CGCG-core motifs on the promoter of the miR-212/miR-132 cluster, overexpression of which has been shown to increase insulin secretion. These motifs are possible targets of calmodulin binding transcription activators Camta1 and Camta2 that have been recognized as integrators of stress responses. We also identified putative NKE elements, possible targets of NK2 homeobox proteins like the essential islet transcription factor Nkx2-2. As Camtas can function as co-activators with NK2 proteins in other tissues, we explored the role of Camta1, Camta2, and Nkx2-2 in the regulation of the miR-212/miR-132 cluster and insulin secretion. We demonstrate that exposure of control Wistar or GK rat islets to 16.7 mM glucose increases miR-212/miR-132 expression but significantly less so in the GK rat. In addition, Camta1, Camta2, and Nkx2-2 were down-regulated in GK rat islets, and knockdown of Camta1 reduced miR-212/miR-132 promoter activity and miR-212/miR-132 expression, even under cAMP elevation. Knockdown of Camta1 decreased insulin secretion in INS-1 832/13 cells and Wistar rat islets but increased insulin content. Furthermore, knockdown of Camta1 reduced K<sup>+</sup>-induced insulin secretion and voltage-dependent Ca<sup>2+</sup> currents. We also demonstrate Camta1 and Nkx2-2 protein interaction. These results indicate that Camta1 is required not only for expression of the miR-212/miR-132 cluster but at multiple levels for regulating beta cell insulin content and secretion.</p>},
  author       = {Mollet, Inês Guerra Uerra and Malm, Helena Anna and Wendt, Anna and Orho-Melander, Marju and Eliasson, Lena},
  issn         = {0021-9258},
  keyword      = {Insulin,calmodulin binding,bioinformatics,rat},
  language     = {eng},
  month        = {08},
  number       = {35},
  pages        = {18440--18452},
  publisher    = {ARRAY(0xb6d60b0)},
  series       = {Journal of Biological Chemistry},
  title        = {Integrator of stress responses calmodulin binding transcription activator 1 (Camta1) Regulates miR-212/miR-132 Expression and insulin secretion},
  url          = {http://dx.doi.org/10.1074/jbc.M116.716860},
  volume       = {291},
  year         = {2016},
}