mRNA Translation

Kasinath, Balakuntalam S.; Mariappan, Meenalakshmi M.; Sataranatarajan, Kavithalakshmi; Lee, Myung Ja; Féliers, Denis

doi:10.1681/asn.2006050488

Cited by 55 publications

(66 citation statements)

References 117 publications

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“…Upon inactivation of GSK3␤ eIF2B⑀ is dephosphorylated on Ser-539 and is free to promote translation initiation. The binding of eIF2 to the activated initiator methionyl tRNA is promoted by dephosphorylated eIF2B⑀ (34,35). High glucose and high insulin reduced eIF2B⑀ Ser-539 phosphorylation starting at 2 h and lasting for up to 48 h (Fig.…”

Section: High Glucose and High Insulin Promote Phosphorylation Andmentioning

confidence: 95%

“…During the elongation phase of translation, amino acids are sequentially added to the nascent peptide chain by the participation of aminoacyl tRNA (34,37). Movement of the ribosome along the mRNA, resulting in translocation of aminoacyl tRNA from the A site to the P site on the ribosome, is regulated by eukaryotic elongation factor 2 (eEF2).…”

Section: High Glucose and High Insulin Regulate Initiation And Elongamentioning

confidence: 99%

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Glycogen Synthase Kinase 3β Is a Novel Regulator of High Glucose- and High Insulin-induced Extracellular Matrix Protein Synthesis in Renal Proximal Tubular Epithelial Cells

Mariappan

Shetty

Sataranatarajan

et al. 2008

Journal of Biological Chemistry

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High glucose (30 mM) and high insulin (1 nM), pathogenic factors of type 2 diabetes, increased mRNA expression and synthesis of laminin ␤1 and fibronectin after 24 h of incubation in kidney proximal tubular epithelial (MCT) cells. We tested the hypothesis that inactivation of glycogen synthase kinase 3␤ (GSK3␤) by high glucose and high insulin induces increase in synthesis of laminin ␤1 via activation of eIF2B⑀. Both high glucose and high insulin induced Ser-9 phosphorylation and inactivation of GSK3␤ at 2 h that lasted for up to 48 h. This was associated with dephosphorylation of eIF2B⑀ and eEF2, and increase in phosphorylation of 4E-BP1 and eIF4E. Expression of the kinase-dead mutant of GSK3␤ or constitutively active kinase led to increased and diminished laminin ␤1 synthesis, respectively. Incubation with selective kinase inhibitors showed that high glucose-and high insulin-induced laminin ␤1 synthesis and phosphorylation of GSK3␤ were dependent on PI 3-kinase, Erk, and mTOR. High glucose and high insulin augmented activation of Akt, Erk, and p70S6 kinase. Dominant negative Akt, but not dominant negative p70S6 kinase, inhibited GSK3␤ phosphorylation induced by high glucose and high insulin, suggesting Akt but not p70S6 kinase was upstream of GSK3␤. Status of GSK3␤ was examined in vivo in renal cortex of db/db mice with type 2 diabetes at 2 weeks and 2 months of diabetes. Diabetic mice showed increased phosphorylation of renal cortical GSK3␤ and decreased phosphorylation of eIF2B⑀, which correlated with renal hypertrophy at 2 weeks, and increased laminin ␤1 and fibronectin protein content at 2 months. GSK3␤ and eIF2B⑀ play a role in augmented protein synthesis associated with high glucose-and high insulin-stimulated hypertrophy and matrix accumulation in renal disease in type 2 diabetes.Glycogen synthase kinase 3␤ (GSK3␤) 3 was originally identified as an enzyme required for the regulation of glycogen metabolism (1). However, it has been found to be involved in a variety of cellular responses including cytoskeletal regulation (2), cell cycle progression (3, 4), apoptosis (5, 6), and cell adhesion (7). GSK3␤ regulation of protein synthesis has not been completely understood. GSK3␤ acts as a switch that regulates both transcription and mRNA translation by controlling the activity of transcription factors and eukaryotic translation initiation factor 2B⑀ (eIF2B⑀), respectively. In the resting cell, GSK3␤ is unphosphorylated and active, inhibiting the activity of its substrates, e.g. eIF2B⑀ and glycogen synthase. Upon stimulation, GSK3␤ is phosphorylated on Ser-9 and inactivated, leading to release of inhibition on activity of its substrates. Several kinases are implicated in Ser-9 phosphorylation of GSK3␤ including p70S6 kinase (8), p90RSK (9), PKC, PKA (10 -12), and Akt (13,14).Augmented protein synthesis contributes to two cardinal manifestations of diabetic kidney disease, i.e. renal hypertrophy and accumulation of extracellular matrix proteins (15). However, the role of GSK3␤ in these events has not been inves...

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Section: High Glucose and High Insulin Promote Phosphorylation Andmentioning

confidence: 95%

Section: High Glucose and High Insulin Regulate Initiation And Elongamentioning

confidence: 99%

Glycogen Synthase Kinase 3β Is a Novel Regulator of High Glucose- and High Insulin-induced Extracellular Matrix Protein Synthesis in Renal Proximal Tubular Epithelial Cells

Mariappan

Shetty

Sataranatarajan

et al. 2008

Journal of Biological Chemistry

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“…The pathways involved in mRNA translation and protein synthesis leading to kidney disease have recently been elegantly reviewed. 68,69 Insights into the role of AMPK on kidney function are in their infancy. However, recent studies suggest AMPK suppression leads to cellular hypertrophy, accumulation of matrix molecules, and mesangial expansion that are hallmarks of obesity-related CKD.…”

Section: Inhibition Of Ampk Triggers the Onset Of Obesity-related Endmentioning

confidence: 99%

Mechanisms Linking Obesity, Chronic Kidney Disease, and Fatty Liver Disease

Sharma

2010

Journal of the American Society of Nephrology

306

213

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“…The mechanisms leading to increment in matrix protein content include an increase in synthesis and inhibition of degradation. High glucose-induced synthesis of matrix proteins can be independently regulated at the levels of transcription (1,2) and mRNA translation (3,4). Elaborate signaling pathways regulate both transcription and translation in the kidney in diabetic mice (2,5,6).…”

mentioning

confidence: 99%