The importance of RNA binding proteins in preproinsulin mRNA stability

Fred, Rikard G.; Welsh, Nils

doi:10.1016/j.mce.2008.06.007

Cited by 23 publications

(20 citation statements)

References 68 publications

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“…A similar stabilizing effect of elevated glucose was observed by Welsh et al (39) on preproinsulin t1 ⁄ 2 (77 h in high glucose versus 29 h in low glucose). It was later discovered that high glucose and cAMP-dependent stabilization of preproinsulin mRNA are likely mediated via translocation of polypyrimidine tract binding protein from the nucleus to the cytoplasm, where it binds the 3Ј UTR of preproinsulin RNA and stabilizes it as part of a multiprotein complex (40). It will be interesting to determine whether a similar mechanism governs Npas4 mRNA stability in beta cells in response to cellular activity.…”

Section: Discussionmentioning

confidence: 99%

Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells

Speckmann

Sabatini

Nian

et al. 2016

Journal of Biological Chemistry

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Cytosolic calcium influx activates signaling pathways known to support pancreatic beta cell function and survival by modulating gene expression. Impaired calcium signaling leads to decreased beta cell mass and diabetes. To appreciate the causes of these cytotoxic perturbations, a more detailed understanding of the relevant signaling pathways and their respective gene targets is required. In this study, we examined the calcium-induced expression of the cytoprotective beta cell transcription factor Npas4. Pharmacological inhibition implicated the calcineurin, Akt/protein kinase B, and Ca 2؉ / calmodulin-dependent protein kinase signaling pathways in the regulation of Npas4 transcription and translation. Both Npas4 mRNA and protein had high turnover rates, and, at the protein level, degradation was mediated via the ubiquitinproteasome pathway. Finally, beta cell cytotoxicity of the calcineurin inhibitor and immunosuppressant tacrolimus (FK-506) was prevented by Npas4 overexpression. These results delineate the pathways regulating Npas4 expression and stability and demonstrate its importance in clinical settings such as islet transplantation.Pancreatic beta cells are critical for the regulation of systemic glycemia because of their ability to sense ambient glucose levels and release the glucose-lowering hormone insulin. The triggering phase of insulin secretion involves glucose uptake into the cell via GLUT1/2, phosphorylation by glucokinase, and metabolism into ATP. This results in the closure of the ATP-sensitive potassium channel, followed by membrane depolarization, calcium influx through L-type voltage-dependent calcium channels and exocytosis of insulin granules (1, 2).In addition to the direct stimulation of insulin secretion, calcium influx also triggers a number of calcium-dependent signaling pathways that promote beta cell function and survival ( Fig. 2A) (3-13). Downstream of these signaling pathways, activation of transcription factors of the CREB, 4 forkhead box protein O (FOXO), and NFAT families mediates gene expression. CREB mediates anti-apoptotic effects in beta cells involving the action of insulin (14) or the incretin hormones (e.g. gastric inhibitory polypeptide and glucagon-like peptide 1) (15, 16), whereas FOXO1 prevents stress-induced beta cell dedifferentiation (17) and reduces glucose-induced oxidative stress (18).In further support of the functional importance of calcium signaling pathways in beta cells, knock out of the regulatory subunit calcineurin b1 of the phosphatase CaN resulted in hypoinsulinemia and hyperglycemia because of reduced beta cell proliferation and mass in aged mice (5). Conditional expression of active NFATc1 (which localizes to the nucleus independently of CaN) rescued the knockout phenotype.The importance of calcineurin activity within human ␤ cells has also been demonstrated during transplantation. Use of the CaN inhibitor tacrolimus (FK-506) as an immunosuppressant results in early graft failure of human islets transplanted into diabetic mice (19), causes beta cell...

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Section: Discussionmentioning

confidence: 99%

Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells

Speckmann

Sabatini

Nian

et al. 2016

Journal of Biological Chemistry

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“…3C), suggesting the observed increase in secretion and intracellular protein accumulation is not caused by an O-GlcNAc-mediated transcriptional mechanism. Insulin mRNA synthesis and translation can be regulated through a variety of mechanisms (3,53,54). Previous work has demonstrated that O-GlcNAc is capable of regulating protein and mRNA stability (55,56).…”

Section: Discussionmentioning

confidence: 99%

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

Durning

Flanagan-Steet

Prasad

et al. 2016

Journal of Biological Chemistry

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The post-translational protein modification O-linked ␤-Nacetylglucosamine (O-GlcNAc) is a proposed nutrient sensor that has been shown to regulate multiple biological pathways. This dynamic and inducible enzymatic modification to intracellular proteins utilizes the end product of the nutrient sensing hexosamine biosynthetic pathway, UDP-GlcNAc, as its substrate donor. Type II diabetic patients have elevated O-GlcNAc-modified proteins within pancreatic beta cells due to chronic hyperglycemia-induced glucose overload, but a molecular role for O-GlcNAc within beta cells remains unclear. Using directed pharmacological approaches in the mouse insulinoma-6 (Min6) cell line, we demonstrate that elevating nuclear O-GlcNAc increases intracellular insulin levels and preserves glucose-stimulated insulin secretion during chronic hyperglycemia. The molecular mechanism for these observed changes appears to be, at least in part, due to elevated O-GlcNAcdependent increases in Ins1 and Ins2 mRNA levels via elevations in histone H3 transcriptional activation marks. Furthermore, RNA deep sequencing reveals that this mechanism of altered gene transcription is restricted and that the majority of genes regulated by elevated O-GlcNAc levels are similarly regulated by a shift from euglycemic to hyperglycemic conditions. These findings implicate the O-GlcNAc modification as a potential mechanism for hyperglycemic-regulated gene expression in the beta cell.

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“…In response to increased glucose metabolism, pre-existing insulin molecules within β-cells are released into the blood stream within minutes, causing an initial peak in blood insulin levels shortly after glucose stimulation. Glucose metabolism further induces the stabilization and translation of pre-existing insulin mRNA, allowing β-cells to produce and secrete more insulin [145]. Insulin levels decrease after this initial peak but remain above their resting state due to this increased production at the post-transcriptional and post-translational level.…”

Section: Figurementioning

confidence: 99%

Intersections of post-transcriptional gene regulatory mechanisms with intermediary metabolism

Arif

Datar

Kalsotra

2017

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Intermediary metabolism studies have typically concentrated on four major regulatory mechanisms—substrate availability, allosteric enzyme regulation, post-translational enzyme modification, and regulated enzyme synthesis. Although transcriptional control has been a big focus, it is becoming increasingly evident that many post-transcriptional events are deeply embedded within the core regulatory circuits of enzyme synthesis/breakdown that maintain metabolic homeostasis. The prominent post-transcriptional mechanisms affecting intermediary metabolism include alternative pre-mRNA processing, mRNA stability and translation control, and the more recently discovered regulation by noncoding RNAs. In this review, we discuss the latest advances in our understanding of these diverse mechanisms at the cell-, tissue- and organismal-level. We also highlight the dynamics, complexity and non-linear nature of their regulatory roles in metabolic decision making, and deliberate some of the outstanding questions and challenges in this rapidly expanding field.

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The importance of RNA binding proteins in preproinsulin mRNA stability

Cited by 23 publications

References 68 publications

Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells

Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

Intersections of post-transcriptional gene regulatory mechanisms with intermediary metabolism

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