Pdx1 (
            <i>MODY4</i>
            ) regulates pancreatic beta cell susceptibility to ER stress

Sachdeva, Mira M.; Claiborn, Kathryn; Khoo, Cynthia; Yang, Juxiang; Groff, David; Mirmira, Raghavendra G.; Stoffers, Doris A.

doi:10.1073/pnas.0904849106

Cited by 207 publications

(192 citation statements)

References 33 publications

(34 reference statements)

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“…Meis family members form heterodimeric and -trimeric complexes with Pbx and/or Pdx1 to regulate gene expression in acinar and ductal cells; however, the potential Meis binding site in the Pdpk1 promoter does not contain nearby consensus-binding sequences for Pbx or Pdx1. Further, Pdpk1 was not dysregulated in cDNA expression arrays examining Pdx1-deficient Min6 and primary islets cells (20). It will be interesting to determine whether Meis3 functions in concert with Pdx1 and/or Pbx family members or as an independent monomeric factor in regulating Pdpk1 gene expression.…”

Section: Discussionmentioning

confidence: 98%

“…Islet isolations from 10-wk-old wild-type C57/Bl6 males were performed using collagenase digestion similarly to previously described protocols (20). After anesthetizing each mouse, the pancreas was inflated with cold 1× Hank's buffer containing 0.2% collagenase (Crescent Chemical).…”

Section: Methodsmentioning

confidence: 99%

“…The protocol was essential as described previously (20). Rabbit anti-Meis3 antiserum and normal rabbit serum (sc-2338, Santa Cruz Biotechnology) were used for the pull-downs.…”

mentioning

confidence: 99%

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Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1

Liu

Wang²,

Birnbaum³

2010

Proc. Natl. Acad. Sci. U.S.A.

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Three-amino-acid-loop-extension (TALE) homeodomain proteins including Meis and Pbx families are generally recognized for their roles in growth and differentiation during vertebrate embryogenesis and tumorigenesis. Whereas genetic studies indicate that Pbx1 regulates the development and function of insulin-producing pancreatic β-cells, the role of Meis family members in β-cells is still unknown. Here we show that Meis3 is abundantly expressed in pancreatic islets and β-cells and that it regulates β-cell survival. We further identify the 3-phosphoinositide-dependent protein kinase 1 (PDK1), a well-known kinase involved in the PI3K-Akt signaling pathway, as a direct Meis3 target, which mediates its role in β-cell survival. This regulatory module appears to function broadly as we also identify Meis3 regulation of cell survival and PDK1 expression in ovarian carcinoma cells, suggesting a unique function for Meis3 beyond the traditional roles for TALE homeodomain factors during embryogenesis.diabetes | transcription | pancreas | apoptosis

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

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Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1

Liu

Wang²,

Birnbaum³

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent findings have established that opening of the MPTP is a component of the ER stress response, including in β-cells (32,33). Sachdeva et al recently reported that Pdx1 deficiency enhances β-cell susceptibility to ER stress-associated apoptosis (34). Thus, accumulated data indicate that the mitochondrial permeability transition plays a significant role in programmed cell death via metabolic shutdown and the ER stress response.…”

Section: Discussionmentioning

confidence: 99%

Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency

Fujimoto¹,

Chen

Polonsky³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mutations of the pancreatic duodenal homeobox gene-1, Pdx1, cause heritable diabetes in humans and mice. A central abnormality with Pdx1 deficiency is increased death of β-cells, leading to decreased β-cell mass. We show that lentiviral suppression of Pdx1 increases death of mouse insulinoma MIN6 β-cells associated with dissipation of the mitochondrial inner membrane electrochemical gradient, Δψ m . Preventing mitochondrial permeability transition pore opening with the cyclophilin D inhibitor cyclosporin A restored Δψ m and rescued cell viability. Reduced β-cell mass, markers of β-cell apoptosis, necrosis, and decreased proliferation are present in Pdx1 haploinsufficient mice. Genetic ablation of the Ppif gene, encoding cyclophilin D, restored β-cell mass and decreased TUNEL and complement complex labeling without affecting β-cell proliferation. In adult mice maintained on a high-fat diet, Ppif ablation normalized fasting glucose and glucose and insulin responses to acute glucose challenge. Thus, cyclophilin D and the mitochondrial permeability transition are critical regulators of β-cell death caused by Pdx1 insufficiency.cell necrosis | apoptosis | insulin

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“…It has been suggested that Atf6 and Xbp1 are "housekeeping" rather than stress response genes in the ␤-cell (53), and our data are consistent with this hypothesis. It was recently reported that islets of Pdx1 (MODY4) haploinsufficient mice are sensitized to ER stress through reduction of Atf4 and its target genes (54), showing that another MODY gene can play an important role in maintenance of ER function as well as ␤-cell development. However, we observed a positive rather than negative effect of DN-Hnf1␣ on Atf4 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Nuclear Factor 1α (HNF1α) Dysfunction Down-regulates X-box-binding Protein 1 (XBP1) and Sensitizes β-Cells to Endoplasmic Reticulum Stress

Kirkpatrick

Wiederkehr

Baquié

et al. 2011

Journal of Biological Chemistry

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Correct endoplasmic reticulum (ER) function is critical for the health of secretory cells, such as the pancreatic ␤-cell, and ER stress is often a contributory factor to ␤-cell death in type 2 diabetes. We have used an insulin-secreting cell line with inducible expression of dominant negative (DN) HNF1␣, a transcription factor vital for correct ␤-cell development and function, to show that HNF1␣ is required for Xbp1 transcription and maintenance of the normal ER stress response. DN HNF1␣ expression sensitizes the ␤-cell to ER stress by directly downregulating Xbp1 transcription, whereas Atf6 is unaffected. Furthermore, DN HNF1␣ alters calcium homeostasis, resulting in elevated cytoplasmic calcium and increased store-operated calcium entry, whereas mitochondrial calcium uptake is normal. Loss of function of XBP1 is toxic to the ␤-cell and decreases production of the ER chaperone BiP, even in the absence of ER stress. DN HNF1␣-induced sensitivity to cyclopiazonic acid can be partially rescued with the chemical chaperone tauroursodeoxycholate. Rat insulin 2 promoter-DN HNF1␣ mouse islets express lower levels of BiP mRNA, synthesize less insulin, and are sensitized to ER stress relative to matched control mouse islets, suggesting that this mechanism is also operating in vivo. Maturity onset diabetes of the young 3 (MODY3)2 is caused by heterozygous mutations in the transcription factor Hnf1␣ (1), which lead to a primary defect in ␤-cell function without insulin resistance. Almost 200 MODY3 mutations in Hnf1␣ have been characterized, with missense mutations occurring most frequently, whereas the appearance of frameshift or nonsense mutations is also observed. MODY3 mutations often act through haploinsufficiency (2), but they can also act through a dominant negative mechanism, as is the case for the (frequently occurring) frameshift mutation P291 fsinsC (3, 4). HNF1␣ was originally discovered as a regulator of hepatic gene expression but has since been found to be expressed in the pancreas (5) and involved in transcription of ␤-cell-specific genes (6, 7). However, genome-wide studies have also demonstrated that its effects on gene expression in the liver and pancreatic islet are strikingly different (8). To characterize the role of HNF1␣ in ␤-cells, a dominant negative (DN) mutant has been used, which carries a substitution of 83 amino acids in its DNA-binding domain, whereas its dimerization domain remains intact (Fig. 1A). This artificial DN mutant forms non-functional dimers with the endogenous protein, preventing it from activating its target genes (9). This has led to the discovery that in insulinsecreting INS-1 cells, suppression of HNF1␣ activity following induction of the DN gene impairs metabolism-secretion coupling (7, 10) and reduces insulin secretion in response to glucose, as well as reducing transcription of the insulin I gene (11). Expression of the transgene also leads to apoptosis in these cells after 48 h of induction (12).During insulin biosynthesis, the nascent chain is translocated into the endop...

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Pdx1 ( MODY4 ) regulates pancreatic beta cell susceptibility to ER stress

Cited by 207 publications

References 33 publications

Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1

Three-amino-acid-loop-extension homeodomain factor Meis3 regulates cell survival via PDK1

Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency

Hepatic Nuclear Factor 1α (HNF1α) Dysfunction Down-regulates X-box-binding Protein 1 (XBP1) and Sensitizes β-Cells to Endoplasmic Reticulum Stress

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