CIDeRGeneral Information:
| Id: | 5,841 |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance |
| Mus musculus | |
| article | |
| Reference: | Landsman L et al.(2011) Elevated Hedgehog/Gli signaling causes beta-cell dedifferentiation in mice Proc. Natl. Acad. Sci. U.S.A. 108 [PMID: 21969560] |
Interaction Information:
| Comment | Increased Hedgehog (Hh) signaling in adult beta-cells, induced by simultaneous expression of an activated form of the GLI2 transcription factor and the elimination of primary cilia in compound transgenic animals, results in glucose intolerance. |
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Formal Description Interaction-ID: 55181 |
process increases_activity of phenotype |
| Comment | Increased Hedgehog (Hh) signaling leads to impaired beta-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice. |
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Formal Description Interaction-ID: 55184 |
process decreases_activity of |
| Comment | Increased Hedgehog (Hh) signaling leads to impaired beta-cell function and insulin secretion, resulting in glucose intolerance in transgenic mice. |
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Formal Description Interaction-ID: 55185 |
process decreases_activity of phenotype reduced pancreatic beta cell function |
| Comment | As expected from previous work showing that elevated Hedgehog (Hh) signaling protects cultured beta-cells from apoptosis, a significant increase in the expression level of the anti-apoptotic gene Bcl2 was detected. |
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Formal Description Interaction-ID: 55186 |
process increases_expression of gene/protein |
| Drugbank entries | Show/Hide entries for BCL2 |
| Comment | The expression level of Kir6.2 and Sur1, components of beta-cell K(ATP) channels required for insulin secretion, was analyzed. Transcript levels of both genes were significantly reduced in TAM-treated transgenic islets compared with control, suggesting potential secretion defects. |
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Formal Description Interaction-ID: 55187 |
process decreases_expression of gene/protein |
| Drugbank entries | Show/Hide entries for KCNJ11 |
| Comment | The expression level of Kir6.2 and Sur1, components of beta-cell K(ATP) channels required for insulin secretion, was analyzed. Transcript levels of both genes were significantly reduced in TAM-treated transgenic islets compared with control, suggesting potential secretion defects. |
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Formal Description Interaction-ID: 55188 |
process decreases_expression of gene/protein |
| Drugbank entries | Show/Hide entries for ABCC8 |
| Comment | Accurate sensing of blood glucose levels is essential for beta-cell function, a process in which the Glucose Transporter 2 (Glut2) plays a key role. Analysis of Glut2 transcript and protein levels revealed a significant reduction in its expression levels in Pdx1-CreER;CLEG2;Kif3af/f transgenic mice compared with control. Immunohistochemical analysis further demonstrated dramatically perturbed Glut2 protein distribution in transgenic islets, implicating defects in glucose sensing. |
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Formal Description Interaction-ID: 55189 |
process decreases_expression of gene/protein |
| Drugbank entries | Show/Hide entries for SLC2A2 |
| Comment | Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype. |
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Formal Description Interaction-ID: 55190 |
process decreases_expression of gene/protein |
| Comment | Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype. |
|
Formal Description Interaction-ID: 55191 |
process decreases_expression of gene/protein |
| Comment | Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype. |
|
Formal Description Interaction-ID: 55192 |
process decreases_expression of gene/protein |
| Comment | Numerous studies have delineated the transcription factor network that guides beta-cell development and ensures proper beta-cell function by maintaining the fully differentiated state of the cells. To study whether the impaired GSIS observed in Pdx1-CreER;CLEG2;Kif3af/f mice was a result of the loss of the mature beta-cell phenotype, the authors analyzed the expression levels of such factors. Transgenic islets expressed lower levels of Pdx1, as shown by significant reduction of both transcript and protein levels compared with nontransgenic control. The analysis further revealed significant reduction in the expression of MafA, NeuroD1, Nkx6.1, and Neurogenin3 (Ngn3) in transgenic islets 4 wk after TAM treatment compared with control. Thus, elevated Hh signaling causes reduction of critical beta-cell markers, suggesting a loss of the mature beta-cell phenotype. |
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Formal Description Interaction-ID: 55193 |
process decreases_expression of gene/protein |
| Comment | Sox9, whose function is required in pancreas progenitor cells, is normally excluded from mature beta-cells. Sox9 transcript and protein levels were increased twofold and fourfold, respectively, in Pdx1-CreER;CLEG2;Kif3af/f transgenic islets compared with control. |
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Formal Description Interaction-ID: 55194 |
process increases_expression of gene/protein |
| Comment | Hes1, a transcription factor activated by the Notch signaling pathway, is expressed in embryonic and adult pancreata but excluded from beta-cells. Pdx1-CreER;CLEG2;Kif3af/f islets showed a twofold increase in Hes1 transcript levels compared with controls, accompanied by a profound up-regulation of the Hes1 protein. |
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Formal Description Interaction-ID: 55195 |
process increases_expression of gene/protein |
| Comment | Prolonged elevation of Hedgehog (Hh) signaling in beta-cells results in development of undifferentiated pancreatic tumors. |
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Formal Description Interaction-ID: 55196 |
process increases_activity of phenotype |