PANDER-induced cell-death genetic networks in islets reveal central role for caspase-3 and cyclin-dependent kinase inhibitor 1A (p21)

Burkhardt, Brant R.; Greene, Scott R.; White, Peter; Wong, Ryan; Brestelli, John; Yang, Jichun; Robert, Claudia E.; Brusko, Todd M.; Wasserfall, Clive; Wu, Jianmei; Atkinson, Mark A.; Gao, Zhiyong; Kaestner, Klaus H.; Wolf, Bryan A.

doi:10.1016/j.gene.2005.10.040

Cited by 24 publications

(32 citation statements)

References 47 publications

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“…Interestingly, Cdkn1a gene expression was downregulated in islets of KsJ mice on HF (Fig. 4 D ), consistent with HF-induced cellular stress, apoptosis (29), and islet loss (Fig. 3 A–C ), whereas Cdkn1a was upregulated by HF in MIP-HSD1 tg/+ , consistent with maintained functionality with reduced cellular stress.…”

Section: Resultssupporting

confidence: 69%

“…MIP-HSD1 tg/+ islets had higher mRNA levels for genes of the small GTPase pathway ( Arf6 , Prkacb , and PKA catalytic subunit β [ PKAβcat ]) linked to enhanced insulin secretion and islet survival (21–23), protein trafficking, turnover, and vesicle docking ( VapB and C , Arf6 , cplx2 , and stx11 ), consistent with the enhanced secretory responses (Fig. 3 E , right, and F and G ) and the mitogen-activated protein kinase/extracellular signal–related kinase (ERK) ( B-raf , Max , and Cdkn1a/p21 ) and Jak/Stat pathways ( Ccnd2 and Jak1 ), indicative of maintained differentiation versus proliferation commitment (24–27) and protection from apoptosis (28,29). MIP-HSD1 tg/+ islets also exhibited higher mRNA levels of genes related to protection from cellular stress ( hspa1a , - a1b , - a4 , and trib3 ) (30).…”

Section: Resultssupporting

confidence: 66%

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Optimal Elevation of β-Cell 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Compensatory Mechanism That Prevents High-Fat Diet–Induced β-Cell Failure

et al. 2012

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Type 2 diabetes ultimately results from pancreatic β-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11β-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic β-cell 11β-HSD1 on insulin secretion, we generated β-cell–specific, 11β-HSD1–overexpressing (MIP-HSD1) mice on a strain background prone to β-cell failure. Unexpectedly, MIP-HSD1tg/+ mice exhibited a reversal of high fat–induced β-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extracellular signal–related kinase and p21 signaling pathways. 11β-HSD1−/− mice showed mild β-cell impairment that was offset by improved glucose tolerance. The benefit of higher β-cell 11β-HSD1 exhibited a threshold because homozygous MIP-HSD1tg/tg mice and diabetic Lepdb/db mice with markedly elevated β-cell 11β-HSD1 levels had impaired basal β-cell function. Optimal elevation of β-cell 11β-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes.

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Section: Resultssupporting

confidence: 69%

Section: Resultssupporting

confidence: 66%

Optimal Elevation of β-Cell 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Compensatory Mechanism That Prevents High-Fat Diet–Induced β-Cell Failure

et al. 2012

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“…This observation confirms and extends earlier findings (8) showing that PANDER, an islet-specific cytokine promoting apoptosis, inhibited p21 expression. Noteworthy, in this study (8), an inverse correlation between p21 and caspase 3 was identified that is in agreement with our present findings showing that in the absence of p21 caspase 3 RT-PCR analysis for p21 expression under the conditions described in (a). GAPDH expression was used as a control for RNA quality.…”

Section: Discussionsupporting

confidence: 92%

Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP

Mihailidou

Chatzistamou

Papavassiliou

et al. 2017

Antioxidants & Redox Signaling

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Aims: Although endoplasmic reticulum (ER) stress is recognized as a major mechanism causing pancreatic dysfunction in diabetes, little is known on how aging modulates the process. Here, we compared the response with ER stress, viability, and insulin release from pancreatic islets of young (6 weeks) or aged (14 months) mice. Results: Islets from aged mice were more sensitive to ER stress than their younger counterparts; they exhibited more pronounced unfolded protein response (UPR) and caspase activation and displayed compromised insulin release after high-glucose stimulation. Genetic ablation of p21 sensitized the islets to ER stress, especially in the aged group, whereas CHOP ablation was protective for islets from both aged and younger animals. Ciclopirox (CPX), an iron chelator that stimulates p21 expression, protected islets from glucotoxicity and mice from dietinduced diabetes, especially in the aged group in a manner that was both p21 and CHOP dependent. Innovation: For the first time, the study shows that age-dependent susceptibility to diet-induced diabetes is associated with the activity of p21 and CHOP in pancreatic islets and that CPX protects islets from glucotoxicity and mice from diabetes in an age-dependent manner. Conclusions: Our results identify ER stress as an age-dependent modifier of islet survival and function by mechanisms implicating enhancement of CHOP activity and inhibition of the protective activity of p21. These findings suggest that interventions restoring the homeostatic activity of ER stress, by agents such as CPX, may be particularly beneficial for the management of diabetes in the elderly. Antioxid. Redox Signal. 27,[185][186][187][188][189][190][191][192][193][194][195][196][197][198][199][200]

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“…Conversely, FAM3B acts profoundly in the regulation of glucose homeostasis. Previous studies have shown that FAM3B is critical to maintain normal pancreatic β-cell function and to induce hepatic gluconeogenic gene expression and glucose output during starvation 18,22–25 .…”

Section: Introductionmentioning

confidence: 99%

FAM3B mediates high glucose-induced vascular smooth muscle cell proliferation and migration via inhibition of miR-322-5p

Zhang

Chen

Zhang

et al. 2017

Sci Rep

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The proliferation and migration of vascular smooth muscle cells (VSMCs) play an essential role during the development of cardiovascular diseases (CVDs). While many factors potentially contribute to the abnormal activation of VSMCs, hyperglycemia is generally believed to be a major causative factor. On the other hand, FAM3B (named PANDER for its secretory form) is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. FAM3B is co-secreted with insulin from the β-cell upon glucose stimulation and regulates glucose homeostasis. In the present study, we sought to determine the roles of FAM3B in the regulation of VSMC physiology, especially under the hyperglycemic condition. We found that FAM3B expression was induced by hyperglycemia both in vivo and in vitro. FAM3B knockdown inhibited, whereas FAM3B overexpression accelerated VSMC proliferation and migration. At the molecular level, FAM3B inhibited miR-322-5p expression, and enforced expression of miR-322-5p antagonized FAM3B-induced VSMC proliferation and migration, suggesting that FAM3B facilitated VSMC pathological activation via miR-322-5p. Taken together, FAM3B mediates high glucose-induced VSMC proliferation and migration via inhibition of miR-322-5p. Thus, FAM3B may therefore serve as a novel therapeutic target for diabetes-related CVDs.

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PANDER-induced cell-death genetic networks in islets reveal central role for caspase-3 and cyclin-dependent kinase inhibitor 1A (p21)

Cited by 24 publications

References 47 publications

Optimal Elevation of β-Cell 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Compensatory Mechanism That Prevents High-Fat Diet–Induced β-Cell Failure

Optimal Elevation of β-Cell 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Compensatory Mechanism That Prevents High-Fat Diet–Induced β-Cell Failure

Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP

FAM3B mediates high glucose-induced vascular smooth muscle cell proliferation and migration via inhibition of miR-322-5p

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