scholarly journals Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period

2007 ◽  
Vol 195 (1) ◽  
pp. 17-27 ◽  
Author(s):  
Gabriel F Anhê ◽  
Tatiane C A Nogueira ◽  
José E Nicoletti-Carvalho ◽  
Camilo Lellis-Santos ◽  
Helena C Barbosa ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Endocrine Pancreas ◽  
Serum Levels ◽  
Serine Phosphorylation ◽  
Calcium Handling ◽  
Signal Transducer ◽  
Functional Changes ◽  
Peripartum Period ◽  
Pregnant State ◽  
Transcription 3

During pregnancy, the maternal endocrine pancreas undergoes, as a consequence of placental lactogens and prolactin (PRL) action, functional changes that are characterized by increased glucose-induced insulin secretion. After delivery, the maternal endocrine pancreas rapidly returns to non-pregnant state, which is mainly attributed to the increased serum levels of glucocorticoids (GCs). Although GCs are known to decrease insulin secretion and counteract PRL action, the mechanisms for these effects are poorly understood. We have previously demonstrated that signal transducer and activator of transcription 3 (STAT3) is increased in islets treated with PRL. In the present study, we show that STAT3 expression and serine phosphorylation are increased in pancreatic islets at the end of pregnancy (P19). STAT3 serine phosphorylation rapidly returned to basal levels 3 days after delivery (L3). The expression of the sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2), a crucial protein involved in the regulation of calcium handling in β-cells, was also increased in P19, returning to basal levels at L3. PRL increased SERCA2 and STAT3 expressions and STAT3 serine phosphorylation in RINm5F cells. The upregulation of SERCA2 by PRL was abolished after STAT3 knockdown. Moreover, PRL-induced STAT3 serine phosphorylation and SERCA2 expression were inhibited by dexamethasone (DEX). Insulin secretion from islets of P19 rats pre-incubated with thapsigargin and L3 rats showed a dramatic suppression of first phase of insulin release. The present results indicate that PRL regulates SERCA2 expression by a STAT3-dependent mechanism. PRL effect is counteracted by DEX and might contribute to the adaptation of maternal endocrine pancreas during the peripartum period.

scholarly journals Adrenal Corticomedullary Mixed Tumor Associated With the FGFR4-G388R Variant

2020 ◽  
Vol 4 (9) ◽  
Author(s):  
Maki Kanzawa ◽  
Hidenori Fukuoka ◽  
Akane Yamamoto ◽  
Kentaro Suda ◽  
Katsumi Shigemura ◽  
...  
Keyword(s):  
Gestational Hypertension ◽  
Immunohistochemical Analysis ◽  
Serine Phosphorylation ◽  
Adrenocortical Adenoma ◽  
Signal Transducer ◽  
Double Immunostaining ◽  
Psychiatric Disturbances ◽  
Peripheral Leukocytes ◽  
Transcription 3 ◽  
Mixed Tumors

Abstract Adrenal corticomedullary mixed tumors (CMMTs) are extremely rare; with only 20 cases being reported to date, the pathogenesis has remained elusive. A 31-year-old woman developed gestational hypertension with psychiatric disturbances persistent to postpartum and was diagnosed with pheochromocytoma, for which adrenalectomy was performed. Histological findings showed mixed adrenocortical adenoma and pheochromocytoma. Double immunostaining of inhibin and INSM1 (insulinoma-associated protein 1) showed that the 2 tumor components had distinct functional properties. Exome analysis of peripheral leukocytes and tumor (singular, as anatomically it is only 1 mass) revealed a homozygous germline FGFR4-G388R variant. As a readout of the variant, serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was detected only in the nucleus of adrenocortical adenoma component but not in the pheochromocytoma component. No tyrosine phosphorylation of STAT3 was detected. We report a case of CMMT with the germline FGFR4-G388R variant. Although additional studies are required, our immunohistochemical analysis suggests that the variant may play a role in the development of the adrenocortical component within the pheochromocytoma, leading to CMMT.

scholarly journals Glucose Intolerance and Impaired Insulin Secretion in Pancreas-Specific Signal Transducer and Activator of Transcription-3 Knockout Mice Are Associated with Microvascular Alterations in the Pancreas

Endocrinology ◽  
2010 ◽  
Vol 151 (5) ◽  
pp. 2050-2059 ◽  
Author(s):  
Elena Kostromina ◽  
Natalia Gustavsson ◽  
Xiaorui Wang ◽  
Chun-Yan Lim ◽  
George K. Radda ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Endocrine Pancreas ◽  
Isolated Islets ◽  
Signal Transducer ◽  
Microvascular Network ◽  
Impaired Insulin Secretion ◽  
Stat3 Signaling ◽  
Impaired Insulin

Maintenance of glucose homeostasis depends on adequate amount and precise pattern of insulin secretion, which is determined by both β-cell secretory processes and well-developed microvascular network within endocrine pancreas. The development of highly organized microvasculature and high degrees of capillary fenestrations in endocrine pancreas is greatly dependent on vascular endothelial growth factor-A (VEGF-A) from islet cells. However, it is unclear how VEGF-A production is regulated in endocrine pancreas. To understand whether signal transducer and activator of transcription (STAT)-3 is involved in VEGF-A regulation and subsequent islet and microvascular network development, we generated a mouse line carrying pancreas-specific deletion of STAT3 (p-KO) and performed physiological analyses both in vivo and using isolated islets, including glucose and insulin tolerance tests, and insulin secretion measurements. We also studied microvascular network and islet development by using immunohistochemical methods. The p-KO mice exhibited glucose intolerance and impaired insulin secretion in vivo but normal insulin secretion in isolated islets. Microvascular density in the pancreas was reduced in p-KO mice, along with decreased expression of VEGF-A, but not other vasotropic factors in islets in the absence of pancreatic STAT3 signaling. Together, our study suggests that pancreatic STAT3 signaling is required for the normal development and maintenance of endocrine pancreas and islet microvascular network, possibly through its regulation of VEGF-A.

scholarly journals Chronic Tumor Necrosis Factor-α Treatment Causes Insulin Resistance via Insulin Receptor Substrate-1 Serine Phosphorylation and Suppressor of Cytokine Signaling-3 Induction in 3T3-L1 Adipocytes

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2994-3003 ◽  
Author(s):  
Ken Ishizuka ◽  
Isao Usui ◽  
Yukiko Kanatani ◽  
Agussalim Bukhari ◽  
Jianying He ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Serine Phosphorylation ◽  
Cytokine Signaling ◽  
Insulin Receptor Substrate ◽  
Signal Transducer ◽  
Suppressor Of Cytokine Signaling ◽  
Transcription 3

Serine phosphorylation of insulin receptor substrate (IRS)-1 and the induction of suppressor of cytokine signaling 3 (SOCS3) is recently well documented as the mechanisms for the insulin resistance. However, the relationship between these two mechanisms is not fully understood. In this study, we investigated the involvement of SOCS3 and IRS-1 serine phosphorylation in TNFα-induced insulin resistance in 3T3-L1 adipocytes. TNFα transiently stimulated serine phosphorylation of IRS-1 from 10 min to 1 h, whereas insulin-stimulated IRS-1 tyrosine phosphorylation was inhibited only after TNFα treatment longer than 4 h. These results suggest that serine phosphorylation of IRS-1 alone is not the major mechanism for the inhibited insulin signaling by TNFα. TNFα stimulation longer than 4 h enhanced the expression of SOCS3 and signal transducer and activator of transcription-3 phosphorylation, concomitantly with the production of IL-6. Anti-IL-6 neutralizing antibody ameliorated suppressed insulin signaling by 24 h TNFα treatment, when it partially decreased SOCS3 induction and signal transducer and activator of transcription-3 phosphorylation. These results suggest that SOCS3 induction is involved in inhibited insulin signaling by TNFα. However, low-level expression of SOCS3 by IL-6 or adenovirus vector did not affect insulin-stimulated IRS-1 tyrosine phosphorylation. Interestingly, when IRS-1 serine phosphorylation was enhanced by TNFα or anisomycin in the presence of low-level SOCS3, IRS-1 degradation was remarkably enhanced. Taken together, both IRS-1 serine phosphorylation and SOCS3 induction are necessary, but one of the pair is not sufficient for the inhibited insulin signaling. Chronic TNFα may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes.

Hypoxia is a potent inducer of the iron masterswitch hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

2017 ◽  
Author(s):  
I Silva ◽  
V Rausch ◽  
T Peccerella ◽  
G Millonig ◽  
HK Seitz ◽  
...  
Keyword(s):  
Signal Transducer ◽  
Potent Inducer ◽  
Transcription 3

Magnesium-dependent Phosphatase (MDP) 1 is a Potential Suppressor of Gastric Cancer

2019 ◽  
Vol 19 (10) ◽  
pp. 817-827
Author(s):  
Jianbo Zhu ◽  
Lijuan Deng ◽  
Baozhen Chen ◽  
Wenqing Huang ◽  
Xiandong Lin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Cell Proliferation ◽  
Protein C ◽  
Biological Function ◽  
Prognostic Markers ◽  
Biological Effects ◽  
Signal Transducer ◽  
Gastric Cancer Cells ◽  
Transcription 3

Background:Recurrence is the leading cause of treatment failure and death in patients with gastric cancer (GC). However, the mechanism underlying GC recurrence remains unclear, and prognostic markers are still lacking.Methods:We analyzed DNA methylation profiles in gastric cancer cases with shorter survival (<1 year) or longer survival (> 3 years), and identified candidate genes associated with GC recurrence. Then, the biological effects of these genes on gastric cancer were studied.Results:A novel gene, magnesium-dependent phosphatase 1 (mdp1), was identified as a candidate gene whose DNA methylation was higher in GC samples from patients with shorter survival and lower in patients with longer survival. MDP1 protein was highly expressed in GC tissues with longer survival time, and also had a tendency to be expressed in highly differentiated GC samples. Forced expression of MDP1 in GC cell line BGC-823 inhibited cell proliferation, whereas the knockdown of MDP1 protein promoted cell growth. Overexpression of MDP1 in BGC-823 cells also enhanced cell senescence and apoptosis. Cytoplasmic kinase protein c-Jun N-terminal kinase (JNK) and signal transducer and activator of transcription 3 (Stat3) were found to mediate the biological function of MDP1.Conclusion:These results suggest that MDP1 protein suppresses the survival of gastric cancer cells and loss of MDP expression may benefit the recurrence of gastric cancer.

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