scholarly journals Human Placental Growth Hormone Increases Expression of the P85 Regulatory Unit of Phosphatidylinositol 3-Kinase and Triggers Severe Insulin Resistance in Skeletal Muscle

Endocrinology ◽  
2004 ◽  
Vol 145 (3) ◽  
pp. 1144-1150 ◽  
Author(s):  
Linda A. Barbour ◽  
Jianhua Shao ◽  
Liping Qiao ◽  
Wayne Leitner ◽  
Marianne Anderson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Normal Pregnancy ◽  
Dominant Negative ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Cellular Mechanisms ◽  
Severe Insulin Resistance ◽  
Placental Growth Hormone ◽  
Glut 4 Translocation ◽  
Phosphatidylinositol 3

Abstract The insulin resistance of normal pregnancy is necessary to divert fuels to the fetus to meet fetal growth demands and is mediated by placental hormones. We recently demonstrated that human placental GH (hPGH) can trigger severe insulin resistance in transgenic (TG) mice. In this study we sought to elucidate the cellular mechanisms by which hPGH interferes with insulin signaling in muscle in TG mice. Insulin-stimulated GLUT-4 translocation to the plasma membrane (PM) was reduced in the TG compared with wild-type (WT) mice (P = 0.05). Insulin receptor (IR) levels were modestly reduced by 19% (P < 0.01) in TG mice, but there were no changes in phosphorylation of IR or IR substrate-1 (IRS-1) between WT and TG mice. A singular finding was a highly significant increase in the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase; P < 0.001), yet a reduced ability of insulin to stimulate IRS-1-associated PI 3-kinase activity (P < 0.05). Although the levels of the p110 catalytic subunit protein of PI 3-kinase and IRS-1 were unchanged in the TG mice, insulin’s ability to stimulate p110 association with IRS-1 was markedly reduced (P < 0.0001). We demonstrate a unique mechanism of insulin resistance and suggest that hPGH may contribute to the insulin resistance of normal pregnancy by increasing the expression of the p85α monomer, which competes in a dominant negative fashion with the p85-p110 heterodimer for binding to IRS-1 protein.

scholarly journals Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation

2006 ◽  
Vol 282 (7) ◽  
pp. 4983-4993 ◽  
Author(s):  
Nandini Ghosh-Choudhury ◽  
Chandi Charan Mandal ◽  
Goutam Ghosh Choudhury
Keyword(s):  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Dominant Negative ◽  
Bone Morphogenetic Protein 2 ◽  
Regulatory Subunit ◽  
Type I ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Morphogenetic Protein ◽  
Phosphatidylinositol 3

Lovastatin promotes osteoblast differentiation by increasing bone morphogenetic protein-2 (BMP-2) expression. We demonstrate that lovastatin stimulates tyrosine phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to an increase in its kinase activity in osteoblast cells. Inhibition of PI3K ameliorated expression of the osteogenic markers alkaline phosphatase, type I collagen, osteopontin, and BMP-2. Expression of dominant-negative PI3K and PTEN, an inhibitor of PI3K signaling, significantly attenuated lovastatin-induced transcription of BMP-2. Akt kinase was also activated in a PI3K-dependent manner. However, our data suggest involvement of an additional signaling pathway. Lovastatin-induced Erk1/2 activity contributed to BMP-2 transcription. Inhibition of PI3K abrogated Erk1/2 activity in response to lovastatin, indicating the presence of a signal relay between them. We provide, as a mechanism of this cross-talk, the first evidence that lovastatin stimulates rapid activation of Ras, which associates with and activates PI3K in the plasma membrane, which in turn regulates Akt and Erk1/2 to induce BMP-2 expression for osteoblast differentiation.

scholarly journals Calcium-induced Human Keratinocyte Differentiation Requires src- and fyn-mediated Phosphatidylinositol 3-Kinase–dependent Activation of Phospholipase C-γ1

2005 ◽  
Vol 16 (7) ◽  
pp. 3236-3246 ◽  
Author(s):  
Zhongjian Xie ◽  
Patrick A. Singleton ◽  
Lilly Y.W. Bourguignon ◽  
Daniel D. Bikle
Keyword(s):  
Phospholipase C ◽  
Tyrosine Phosphorylation ◽  
Dominant Negative ◽  
Keratinocyte Differentiation ◽  
Regulatory Subunit ◽  
Alternative Mechanism ◽  
Phosphatidylinositol 3 Kinase ◽  
Differentiation Markers ◽  
Human Keratinocyte ◽  
Phosphatidylinositol 3

We have previously demonstrated that phospholipase C (PLC)-γ1 is required for calcium-induced human keratinocyte differentiation. In the present study, we investigated whether the activation of PLC-γ1 by nonreceptor kinases such as src and fyn plays a role in mediating this process. Our results showed that the combination of dominant negative src and fyn blocked calcium-stimulated PLC-γ1 activity and human keratinocyte differentiation, whereas each separately has little effect. However, unlike the activation of PLC-γ1 by epidermal growth factor, calcium-induced activation of PLC-γ1 was not a result of direct tyrosine phosphorylation. Therefore, we examined an alternative mechanism, in particular phosphatidylinositol 3,4,5-triphosphate (PIP3) formed as a product of phosphatidylinositol 3-kinase (PI3K) activity. PIP3 binds to and activates PLC-γ1. The combination of dominant negative src and fyn blocked calcium-induced tyrosine phosphorylation of the regulatory subunit of PI3K, p85α, and the activity of the catalytic subunit of PI3K. PI3K inhibitors blocked calcium activation of PLC-γ1 as well as the induction of keratinocyte differentiation markers involucrin and transglutaminase. These data indicate that calcium activates PLC-γ1 via increased PIP3 formation mediated by c-src– and fyn-activated PI3K. This activation is required for calcium-induced human keratinocyte differentiation.

scholarly journals Homocysteine thiolactone inhibits insulin signaling, and glutathione has a protective effect

2001 ◽  
Vol 27 (1) ◽  
pp. 85-91 ◽  
Author(s):  
S Najib ◽  
V Sanchez-Margalet
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Glycogen Synthesis ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Homocysteine Thiolactone ◽  
Phosphatidylinositol 3

Hyperhomocysteinemia and insulin resistance are independent factors for cardiovascular disease. Most of the angiotoxic effects of homocysteine are related to the formation of homocysteine thiolactone and the consequent increase in oxidative stress. The oxidative stress has also been shown to impair insulin action, therefore leading to insulin resistance. In order to study a putative direct effect of homocysteine on insulin signaling, we have characterized the molecular counter-regulation of the early events in the signal transduction of the insulin receptor, and the metabolic end-point of glycogen synthesis. We employed HTC rat hepatoma cells transfected with the human insulin receptor. A 10 min exposure to homocysteine thiolactone (50 microM) resulted in a significant inhibition of insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and its substrates IRS-1 and p60-70, as well as their association with the p85 regulatory subunit of phosphatidylinositol 3-kinase. These effects led to impairment of the insulin-stimulated phosphatidylinositol 3-kinase activity, which plays a central role in regulating insulin action. Thus, insulin-stimulated glycogen synthesis was also inhibited by homocysteine thiolactone. To investigate whether oxidative stress was mediating the counter-regulatory effect of homocysteine thiolactone on insulin signaling, we preincubated the cells (5 min) with 250 microM glutathione prior to the incubation with homocysteine (10 min) and subsequent insulin challenge. Glutathione completely abolished the effects of homocysteine thiolactone on insulin-receptor signaling and restored the insulin-stimulated glycogen synthesis. In conclusion, these data suggest that homocysteine thiolactone impairs insulin signaling by a mechanism involving oxidative stress, leading to a defect in insulin action.

Association with Longevity of Phosphatidylinositol 3-Kinase Regulatory Subunit 1 Gene Variants Stems from Protection against Mortality Risk in Men with Cardiovascular Disease

Gerontology ◽  
2021 ◽  
pp. 1-9
Author(s):  
Timothy A. Donlon ◽  
Randi Chen ◽  
Kamal H. Masaki ◽  
Bradley J. Willcox ◽  
Brian J. Morris
Keyword(s):  
Cardiovascular Disease ◽  
Life Span ◽  
Mortality Risk ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Survival Curves ◽  
Genotypic Effect ◽  
Hazard Ratios ◽  
Phosphatidylinositol 3

<b><i>Introduction:</i></b> Genetic variation in the phosphatidylinositol 3-kinase reregulatory subunit 1 gene (<i>PIK3R1</i>) is associated with longevity. <b><i>Objective:</i></b> The aim of the study was to determine whether cardiovascular disease (CVD) affects this association. <b><i>Methods:</i></b> We performed a longitudinal study of longevity-associated <i>PIK3R1</i> single-nucleotide polymorphism <i>rs7709243</i> genotype by CVD status in 3,584 elderly American men of Japanese ancestry. <b><i>Results:</i></b> At baseline (1991–1993), 2,254 subjects had CVD and 1,314 did not. The follow-up until Dec 31, 2019 found that overall, men with a CVD had higher mortality than men without a CVD (<i>p</i> = 1.7 × 10<sup>−5</sup>). However, survival curves of CVD subjects differed according to <i>PIK3R1</i> genotype. Those with longevity-associated <i>PIK3R1 TT</i>/<i>CC</i> had survival curves similar to those of subjects without a CVD (<i>p</i> = 0.11 for <i>TT</i>/<i>CC</i>, and <i>p</i> = 0.054 for <i>TC</i>), whereas survival curves for CVD subjects with the <i>CT</i> genotype were significantly attenuated compared with survival curves of subjects without a CVD (<i>p</i> = 0.0000012 compared with <i>TT</i>/<i>CC</i>, and <i>p</i> = 0.0000028 compared with <i>TC</i>). Men without CVD showed no association of longevity-associated genotype with life span (<i>p</i> = 0.58). Compared to subjects without any CVD, hazard ratios for mortality risk were 1.26 (95% CI, 1.14–1.39; <i>p</i> = 0.0000043) for <i>CT</i> subject with CVD and 1.07 (95% CI 0.99–1.17; <i>p</i> = 0.097) for <i>CC</i>/<i>TT</i> subjects with CVD. There was no genotypic effect on life span for 1,007 subjects with diabetes and 486 with cancer. <b><i>Conclusion:</i></b> Our study provides novel insights into the basis for <i>PIK3R1</i> as a longevity gene. We suggest that the <i>PIK3R1</i> longevity genotype attenuates mortality risk in at-risk individuals by protection against cellular stress caused by CVD.

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