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p38 MAPK ATTENUATES INSULIN SIGNALING BY INHIBITING IRS1 TYROSINE PHOSPHORYLATION IN IRS1 OVEREXPRESSED 293T CELLS

Yıl 2020, Cilt: 13 Sayı: 1, 19 - 24, 30.04.2020

Öz

Objective: The aim of this study was to investigate the effect of p38 MAPK on insulin signaling in IRS1 overexpressed 293T cells.
Materials and Methods: 293T cells were transfected with pcDNA3.1flag-tagged-human-IRS1 expression vector. Anisomycin and SB203580 were used as p38 MAPK activator and inhibitor respectively. Expression and phosphorylation profiles of IRS1, AKT and ERK1/2 were detected by western blotting.
Results: Anisomycin treatment led to decrease in insulin induced tyrosine phosphorylation of IRS1 through Ser/Thr phosphorylations. We also detected insulin induced AKT and ERK1/2 phosphorylations reduced by anisomycin compared to insulin treated group. We observed that negative effects of anisomycin on insulin signaling reversed by the treatment of SB203580.
Conclusion: p38 MAPK inhibits the phosphorylations of IRS1, AKT and ERK1/2. p38 MAPK may serve as a therapeutic target for insulin resistance and specific p38 MAPK inhibitors might be potential and promising agents for the therapeutic approaches.

Destekleyen Kurum

Akdeniz University, The Scientific Research Projects Coordination Unit

Proje Numarası

2012.03.0122.004

Teşekkür

This study was supported by a grant from Akdeniz University, The Scientific Research Projects Coordination Unit (Project No: 2012.03.0122.004), Antalya, Turkey.

Kaynakça

  • Boura-Halfon S, Zick Y. Phosphorylation of IRS proteins, insulin action, and insulin resistance. American journal of physiology. Endocrinology and Metabolism. 2009;296: 581-591.
  • Cao W, Collins QF, Becker TC, Robidoux J, Lupo EG Jr et al. p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis. J Biol Chem. 2005; 280(52):42731-42737.
  • Collins QF, Xiong Y, Lupo EG Jr, Liu HY, Cao W. p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. J Biol Chem. 2006;281(34):24336-24344.
  • Copps KD, White MF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 2012;55:2565-2582.
  • Cuenda A. p38 MAP-Kinases pathway regulation, function and role in human diseases. Biochimica et Biophysica Acta. 2007;1773:1358-1375.
  • Fang P, Sun Y, Gu X, Shi M, Bo P et al. Baicalin ameliorates hepatic insulin resistance and gluconeogenic activity through inhibition of p38 MAPK/PGC-1α pathway. Phytomedicine. 2019;64:153074.
  • Feifel E, Obexer P, Andratsch M, Euler S, Taylor L et al. p38 MAPK mediates acid-induced transcription of PEPCK in LLC-PK(1)-FBPase(+) cells. Am. J. Physiol. Renal. Physiol. 2002;283(4):678-688.
  • Geiger PC, Wright DC, Han D-H, Holloszy JO. Activation of p38 MAP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab. 2005;288:782– 788.
  • Gorgisen G, Balci MK, Celik FC, Gokkaya M, Ozdem S et al. Differential activation and expression of IRS1 in mononuclear cells of type 2 diabetes patients after insulin stimulation. Cell Mol Biol (Noisy-le-grand). 2016;62(2):25-30.
  • Gorgisen G, Gulacar IM, Ozes ON. The role of insulin receptor substrate (IRS) proteins in oncogenic transformation. Cell Mol Biol (Noisy-le-grand). 2017;63(1):1-5.
  • Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol. 2014;220(2):1-23.
  • Hancer NJ, Qiu W, Cherella C, Li Y, Copps KD et al. Insulin and metabolic stress stimulate multisite serine/ threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation. The Journal of Biological Chemistry 2014;289: 12467-12484.
  • Hemi R, Yochananov Y, Barhod E, Kasher-Meron M, Karasik A et al. p38 Mitogen-activated protein kinase-dependent transactivation of ErbB receptor family a novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance. Diabetes. 2011;60(4):1134-45.
  • Hiratani K, Haruta T, Tani A, Kawahara J, Usui I et al. Roles of mTOR and JNK in serine phosphorylation, translocation, and degradation of IRS-1. Biochemical and Biophysical Research Communications. 2005;335:836–842.
  • Liu S, Xu R, Gerin I et al. SRA regulates adipogenesis by modulating p38/JNK phosphorylation and stimulating insulin receptor gene expression and downstream signaling. Plos One. 2014;9:e95416.
  • Liu Z, Cao W. p38 Mitogen-activated protein kinase: A Critical node linking insulin resistance and cardiovascular diseases in type 2 diabetes. Endocrine Metabolic & Immune Disorders - Drug Targets. 2009;9(1):38-46.
  • McGee SL, Hargreaves M. Exercise and skeletal muscle glucose transporter 4 expression: molecular mechanisms. Clin Exp Pharmacol Physiol. 2006,33:395–399.
  • Miller WP, Ravi S, Martin TD, Kimball SR, Dennis MD. Activation of the stress response kinase JNK (c-Jun N-terminal Kinase) attenuates insulin action in retina through a p70S6K1-dependent mechanism. J Biol Chem. 2017;292(5):1591-1602.
  • Park HS, Kim MS, Huh SH, Pak J, Chung J et al. Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. J Biol Chem. 2002;277(4):2573-8.
  • Pereira S, Yu WQ, Moore J, Mori Y, Tsiani E et al Effect of a p38 MAPK inhibitor on FFA-induced hepatic insulin resistance In vivo. Nutr Diabetes. 2016;6:e210.
  • Schindler JF, Monahan JB, Smith WG. p38 pathway kinases as anti-inflammatory drug targets. J Dent Res. 2007;86:800–811 Tanti JF, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Current Opinion in Pharmacology 2009;9:753-762.
  • Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T et al. A phosphatidylinositol 3-kinase/Akt/ mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proceedings of the National Academy of Sciences of the United States of America 2001;98:4640-4645
  • Wang S, Ding L, Ji H, Xu Z, Liu Q et al. Role of p38 MAPK in the Development of Diabetic Cardiomyopathy Int J Mol Sci. 2016;17(7):1037.
  • Zhang C, Huang Z, Gu J, Yan X, Lu X et al. Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signaling pathway. Diabetologia. 2015;58:1937–1948.

p38 MAPK, IRS1 EKSPRESYONU ARTTIRILMIŞ 293T HÜCRELERİNDE IRS1 TİROZİN FOSFORİLASYONUNU İNHİBE EDEREK İNSÜLİN SİNYALİNİ YAVAŞLATMAKTADIR

Yıl 2020, Cilt: 13 Sayı: 1, 19 - 24, 30.04.2020

Öz

Amaç: Bu çalışmanın amacı IRS1 ekspresyonu arttırılmış 293T hücrelerinde p38 MAPK’ ın insülin sinyali üzerindeki etkisinin belirlenmesidir.
Materyal Metod: 293T hücreleri pcDNA3.1flag-tagged-insan-IRS1 ekspresyon vektörü ile transfekte edilmiştir. P38 MAPK inhibitörü ve aktivatörü olarak sırasıyla anisomisin ve SB203580 kullanılmıştır. IRS1, AKT ve ERK1/2 ekspresyon ve aktivasyon profilleri western blot ile belirlenmiştir.
Bulgular: Anisomisin muamelesi IRS1 Ser/Thr fosforilasyonu aracılığıyla insülin indüklü IRS1 tirozin fosforilasyonunu azalmıştır. Anisomisin muamele grupta kontrol grubuna oranla insülin indüklü AKT ve ERK1/2 fosforilasyonunda da azalma olduğu belirlenmiştir. Anisomisinin insülin sinyali üzerindeki negatif etkilerinin SB203580 muamelesi ile geri döndürüldüğü gözlemlenmiştir.
Sonuç: p38 MAPK, IRS1, AKT ve ERK1/2 fosforilasyonlarını inhibe etmektedir. P38 MAPK, insülin direncinde terapötik hedef olarak kullanılabilir ve spesifik p38 MAPK inhibitörleri, terapötik yaklaşımlar için potansiyel ve umut verici ajanlar olabilir.

Proje Numarası

2012.03.0122.004

Kaynakça

  • Boura-Halfon S, Zick Y. Phosphorylation of IRS proteins, insulin action, and insulin resistance. American journal of physiology. Endocrinology and Metabolism. 2009;296: 581-591.
  • Cao W, Collins QF, Becker TC, Robidoux J, Lupo EG Jr et al. p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis. J Biol Chem. 2005; 280(52):42731-42737.
  • Collins QF, Xiong Y, Lupo EG Jr, Liu HY, Cao W. p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. J Biol Chem. 2006;281(34):24336-24344.
  • Copps KD, White MF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 2012;55:2565-2582.
  • Cuenda A. p38 MAP-Kinases pathway regulation, function and role in human diseases. Biochimica et Biophysica Acta. 2007;1773:1358-1375.
  • Fang P, Sun Y, Gu X, Shi M, Bo P et al. Baicalin ameliorates hepatic insulin resistance and gluconeogenic activity through inhibition of p38 MAPK/PGC-1α pathway. Phytomedicine. 2019;64:153074.
  • Feifel E, Obexer P, Andratsch M, Euler S, Taylor L et al. p38 MAPK mediates acid-induced transcription of PEPCK in LLC-PK(1)-FBPase(+) cells. Am. J. Physiol. Renal. Physiol. 2002;283(4):678-688.
  • Geiger PC, Wright DC, Han D-H, Holloszy JO. Activation of p38 MAP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab. 2005;288:782– 788.
  • Gorgisen G, Balci MK, Celik FC, Gokkaya M, Ozdem S et al. Differential activation and expression of IRS1 in mononuclear cells of type 2 diabetes patients after insulin stimulation. Cell Mol Biol (Noisy-le-grand). 2016;62(2):25-30.
  • Gorgisen G, Gulacar IM, Ozes ON. The role of insulin receptor substrate (IRS) proteins in oncogenic transformation. Cell Mol Biol (Noisy-le-grand). 2017;63(1):1-5.
  • Guo S. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol. 2014;220(2):1-23.
  • Hancer NJ, Qiu W, Cherella C, Li Y, Copps KD et al. Insulin and metabolic stress stimulate multisite serine/ threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation. The Journal of Biological Chemistry 2014;289: 12467-12484.
  • Hemi R, Yochananov Y, Barhod E, Kasher-Meron M, Karasik A et al. p38 Mitogen-activated protein kinase-dependent transactivation of ErbB receptor family a novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance. Diabetes. 2011;60(4):1134-45.
  • Hiratani K, Haruta T, Tani A, Kawahara J, Usui I et al. Roles of mTOR and JNK in serine phosphorylation, translocation, and degradation of IRS-1. Biochemical and Biophysical Research Communications. 2005;335:836–842.
  • Liu S, Xu R, Gerin I et al. SRA regulates adipogenesis by modulating p38/JNK phosphorylation and stimulating insulin receptor gene expression and downstream signaling. Plos One. 2014;9:e95416.
  • Liu Z, Cao W. p38 Mitogen-activated protein kinase: A Critical node linking insulin resistance and cardiovascular diseases in type 2 diabetes. Endocrine Metabolic & Immune Disorders - Drug Targets. 2009;9(1):38-46.
  • McGee SL, Hargreaves M. Exercise and skeletal muscle glucose transporter 4 expression: molecular mechanisms. Clin Exp Pharmacol Physiol. 2006,33:395–399.
  • Miller WP, Ravi S, Martin TD, Kimball SR, Dennis MD. Activation of the stress response kinase JNK (c-Jun N-terminal Kinase) attenuates insulin action in retina through a p70S6K1-dependent mechanism. J Biol Chem. 2017;292(5):1591-1602.
  • Park HS, Kim MS, Huh SH, Pak J, Chung J et al. Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. J Biol Chem. 2002;277(4):2573-8.
  • Pereira S, Yu WQ, Moore J, Mori Y, Tsiani E et al Effect of a p38 MAPK inhibitor on FFA-induced hepatic insulin resistance In vivo. Nutr Diabetes. 2016;6:e210.
  • Schindler JF, Monahan JB, Smith WG. p38 pathway kinases as anti-inflammatory drug targets. J Dent Res. 2007;86:800–811 Tanti JF, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Current Opinion in Pharmacology 2009;9:753-762.
  • Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T et al. A phosphatidylinositol 3-kinase/Akt/ mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proceedings of the National Academy of Sciences of the United States of America 2001;98:4640-4645
  • Wang S, Ding L, Ji H, Xu Z, Liu Q et al. Role of p38 MAPK in the Development of Diabetic Cardiomyopathy Int J Mol Sci. 2016;17(7):1037.
  • Zhang C, Huang Z, Gu J, Yan X, Lu X et al. Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signaling pathway. Diabetologia. 2015;58:1937–1948.
Toplam 24 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Klinik Tıp Bilimleri
Bölüm Orijinal Araştırma Makaleleri
Yazarlar

Gökhan Görgişen

Osman Nidai Ozes

Proje Numarası 2012.03.0122.004
Yayımlanma Tarihi 30 Nisan 2020
Gönderilme Tarihi 28 Ocak 2020
Yayımlandığı Sayı Yıl 2020 Cilt: 13 Sayı: 1

Kaynak Göster

APA Görgişen, G., & Ozes, O. N. (2020). p38 MAPK ATTENUATES INSULIN SIGNALING BY INHIBITING IRS1 TYROSINE PHOSPHORYLATION IN IRS1 OVEREXPRESSED 293T CELLS. Van Sağlık Bilimleri Dergisi, 13(1), 19-24.

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