Corneal Cell Survival in Adenovirus Type 19 Infection Requires Phosphoinositide 3-Kinase/Akt Activation

Rajala, Maitreyi S.; Rajala, Raju V S; Astley, Roger; Butt, Amir L.; Chodosh, James

doi:10.1128/jvi.79.19.12332-12341.2005

Cited by 37 publications

(49 citation statements)

References 51 publications

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“…Ras is an important mediator of anti-apoptotic signals induced by survival factors and promotes survival of many cell systems by activating the PI 3-kinase/PKB pathway (26,27). Role of Ras in increased glucose uptake has been previously reported (28), and other adenoviruses have been reported to activate Ras or PI 3-kinase (18,29,30). However, effect of these adenoviruses on glucose uptake by HSKM cells is unknown.…”

Section: Discussionmentioning

confidence: 99%

Human Adenovirus Type 36 Enhances Glucose Uptake in Diabetic and Nondiabetic Human Skeletal Muscle Cells Independent of Insulin Signaling

et al. 2008

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OBJECTIVE-Human adenovirus type 36 (Ad-36) increases adiposity but improves insulin sensitivity in experimentally infected animals. We determined the ability of Ad-36 to increase glucose uptake by human primary skeletal muscle (HSKM) cells. RESEARCH DESIGN AND METHODS-The effect of Ad-36 on glucose uptake and cell signaling was determined in HSKM cells obtained from type 2 diabetic and healthy lean subjects. Ad-2, another human adenovirus, was used as a negative control. Gene expression and proteins of GLUT1 and GLUT4 were measured by real-time PCR and Western blotting. Role of insulin and Ras signaling pathways was determined in Ad-36 -infected HSKM cells. RESULTS-Ad-36and Ad-2 infections were confirmed by the presence of respective viral mRNA and protein expressions. In a dose-dependent manner, Ad-36 significantly increased glucose uptake in diabetic and nondiabetic HSKM cells. Ad-36 increased gene expression and protein abundance of GLUT1 and GLUT4, GLUT4 translocation to plasma membrane, and phosphatidylinositol 3-kinase (PI 3-kinase) activity in an insulin-independent manner. In fact, Ad-36 decreased insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and IRS-1-and IRS-2-associated PI 3-kinase activities. On the other hand, Ad-36 increased Ras gene expression and protein abundance, and Ras siRNA abrogated Ad-36 -induced PI 3-kinase activation, GLUT4 protein abundance, and glucose uptake. These effects were not observed with Ad-2 infection.CONCLUSIONS-Ad-36 infection increases glucose uptake in HSKM cells via Ras-activated PI 3-kinase pathway in an insulinindependent manner. These findings may provide impetus to exploit the role of Ad-36 proteins as novel therapeutic targets for improving glucose handling.

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Section: Discussionmentioning

confidence: 99%

Human Adenovirus Type 36 Enhances Glucose Uptake in Diabetic and Nondiabetic Human Skeletal Muscle Cells Independent of Insulin Signaling

et al. 2008

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“…5A and B). PI3K activation is also required for cellular entry by some adenoviruses (43,44), but not all (45), and human adenoviruses such as Ad-5, Ad-9, and Ad-19 are known to activate PI3K (45)(46)(47)(48). Since the adipose tissue was infected with Ad-36 before Wortmannin treatment, the effect of PI3K inhibition on cellular entry of Ad-36 was not relevant.…”

Section: Discussionmentioning

confidence: 99%

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36

et al. 2008

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OBJECTIVE-Experimental infection of rats with human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as a therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue. RESEARCH DESIGN AND METHODS-We determinedwhether Ad-36 increases glucose uptake in human adipose tissue explants. Cell-signaling pathways targeted by Ad-36 to increase glucose uptake were determined in the explants and human adipose-derived stem cells. Ad-2, a nonadipogenic human adenovirus, was used as a negative control. As a proof of concept, nondiabetic and diabetic subjects were screened for the presence of Ad-36 antibodies to ascertain if natural Ad-36 infection predicted improved glycemic control.RESULTS-Ad-36 increased glucose uptake by adipose tissue explants obtained from nondiabetic and diabetic subjects. Without insulin stimulation, Ad-36 upregulated expressions of several proadipogenic genes, adiponectin, and fatty acid synthase and reduced the expression of inflammatory cytokine macrophage chemoattractant protein-1 in a phosphotidylinositol 3-kinase (PI3K)-dependent manner. In turn, the activation of PI3K by Ad-36 was independent of insulin receptor signaling but dependent on Ras signaling recruited by Ad-36. Ad-2 was nonadipogenic and did not increase glucose uptake. Natural Ad-36 infection in nondiabetic and diabetic subjects was associated with significantly lower fasting glucose levels and A1C, respectively. CONCLUSIONS-Ad-36 proteins may provide novel therapeutic targets that remodel human adipose tissue to a more metabolically favorable profile.

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“…18,31 Ad-9 significantly increases lipid accumulation in 3T3-L1 cells 32 and its E4 orf-1 gene shares 92% homology with amino-acid sequence of Ad-36 E4 orf1, but its in vivo adipogenic effect is unknown. Ad-19, Ad-5 vector induce PI3K pathway 33,34 but their adipogenic genes are not yet identified.…”

Section: Discussionmentioning

confidence: 99%

Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene

et al. 2007

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Objective: Understanding the regulation of adipocyte differentiation by cellular and extracellular factors is crucial for better management of chronic conditions such as obesity, insulin resistance and lipodystrophy. Experimental infection of rats with a human adenovirus type 36 (Ad-36) improves insulin sensitivity and promotes adipogenesis, reminiscent of the effect of thiozolinediones. Therefore, we investigated the role of Ad-36 as a novel regulator of the adipogenic process. Design and Results: Even in the absence of adipogenic inducers, infection of 3T3-L1 preadipocytes and human adipose-derived stem cells (hASC) by Ad-36, but not Ad-2 that is another human adenovirus, modulated regulatory points that spanned the entire adipogenic cascade ranging from the upregulation of cAMP, phosphatidylinositol 3-kinase and p38 signaling pathways, downregulation of Wnt10b expression, and increased expression of CCAAT/enhancer binding protein-b and peroxisome proliferator-activated receptor g2 and consequential lipid accumulation. Next, we identified that E4 open reading frame (orf)-1 gene of the virus is necessary and sufficient for Ad-36-induced adipogenesis. Selective knockdown of E4 orf-1 by RNAi abrogated Ad-36-induced adipogenic signaling cascade in 3T3-L1 cells and hASC. Compared to the null vector, selective expression of Ad-36 E4 orf-1 in 3T3-L1 induced adipogenesis, which was abrogated when the PDZ-binding domain of the protein was deleted. Conclusion: Thus, Ad-36 E4 orf-1 is a novel inducer of rodent and human adipocyte differentiation process.

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Corneal Cell Survival in Adenovirus Type 19 Infection Requires Phosphoinositide 3-Kinase/Akt Activation

Cited by 37 publications

References 51 publications

Human Adenovirus Type 36 Enhances Glucose Uptake in Diabetic and Nondiabetic Human Skeletal Muscle Cells Independent of Insulin Signaling

Human Adenovirus Type 36 Enhances Glucose Uptake in Diabetic and Nondiabetic Human Skeletal Muscle Cells Independent of Insulin Signaling

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36

Human adenovirus Ad-36 induces adipogenesis via its E4 orf-1 gene

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