Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells

Riesterer, Oliver; Zingg, Daniel; Hummerjohann, Jörg; Bodis, Stephan; Pruschy, Martin

doi:10.1038/sj.onc.1207596

Cited by 68 publications

(64 citation statements)

References 54 publications

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“…On the other hand, mTORC1 inhibitors have been shown to inhibit proliferation of vascular endothelial cells (29). Riesterer et al (17) reported that inhibition of mTOR by rapamycin induced endothelial cell death through caspase 3 activation and treatment-dependent degradation of Akt protein. Some angiogenic vessels in adenomas showed the mTORC1 signal activation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that the intestinal polyp inhibition by RAD001 was independent of the suppression of angiogenesisrelated factors such as VEGF in Apc ⌬716 mice. It is also reported that rapamycin directly inhibits endothelial cell growth (17,18). Accordingly, we examined p-S6-positive endothelial cells in adenoma blood vessels by double immunostaining for p-S6, and CD31, a marker of endothelial cells.…”

Section: Inhibitory Effect Of Rad001 On Polyp Formation Is Attributabmentioning

confidence: 99%

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Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice

Fujishita

Aoki

Lane

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

150

143

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The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth via mTOR complex 1 (mTORC1), whose activation has been implicated in many human cancers. However, mTORC1's status in gastrointestinal tumors has not been characterized thoroughly. We have found that the mTORC1 pathway is activated with increased expression of the mTOR protein in intestinal polyps of the Apc ⌬716 heterozygous mutant mouse, a model for human familial adenomatous polyposis. An 8-week treatment with RAD001 (everolimus) suppressed the mTORC1 activity in these polyps and inhibited proliferation of the adenoma cells as well as tumor angiogenesis, which significantly reduced not only the number of polyps but also their size. ␤-Catenin knockdown in the colon cancer cell lines reduced the mTOR level and thereby inhibited the mTORC1 signaling. These results suggest that the Wnt signaling contributes to mTORC1 activation through the increased level of mTOR and that the activation plays important roles in the intestinal polyp formation and growth. Indeed, longterm RAD001 treatment significantly reduced mortality of the Apc ⌬716 mice. Thus, we propose that the mTOR inhibitors may be efficacious for therapy and prevention of colonic adenomas and cancers with Wnt signaling activation.adenoma ͉ colon cancer ͉ mammalian target of rapamycin ͉ RAD001 ͉ rapamycin

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Section: Discussionmentioning

confidence: 99%

Section: Inhibitory Effect Of Rad001 On Polyp Formation Is Attributabmentioning

confidence: 99%

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice

Fujishita

Aoki

Lane

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

150

143

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“…However, we found that MULAN-induced Akt degradation was independent of Hsp90 inhibitor-induced Akt degradation. Riesterer et al [42] reported that the inhibition of vascular endothelial growth factor (VEGF) signaling by the VEGF inhibitor PTK787/Zk222584 results in the specific degradation of cellular Akt by UPS. In addition, rapamycin, which inhibits the mammalian target of rapamycin, also abrogates the VEGF-protective effect on UPS-mediated Akt degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Several reports have described UPS-mediated Akt proteolytic degradation in different types of cells [42]. Akt is stabilized in the presence of Hsp90, and Hsp90 inhibitors induce Akt degradation [18].…”

Section: Discussionmentioning

confidence: 99%

Akt is negatively regulated by the MULAN E3 ligase

et al. 2012

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“…One such mechanism is Akt degradation (18). VEGF deprivation (19) or TNF-␣ treatment (20) caused Akt degradation through the UPS and caspases, leading to endothelial cell death or insulin signaling impairment, respectively. In addition, Akt degradation through the UPS plays a physiological role in formation of neuronal polarity (21).…”

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confidence: 99%

Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

Kim

Lee

Huh

et al. 2011

Journal of Biological Chemistry

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Emphysema is one of the characteristic features of chronic obstructive pulmonary disease, which is caused mainly by cigarette smoking. Recent data have suggested that apoptosis and cell cycle arrest may contribute to the development of emphysema. In this study, we addressed the question of whether and how cigarette smoke affected Akt, which plays a critical role in cell survival and proliferation. In normal human lung fibroblasts, cigarette smoke extract (CSE) caused cell death, accompanying degradation of total and phosphorylated Akt (p-Akt), which was inhibited by MG132. CSE exposure resulted in preferential ubiquitination of the active Akt (myristoylated), rather than the inactive (T308A/S473A double mutant) Akt. Consistent with cytotoxicity, CSE induced a progressive decrease of phosphorylated human homolog of mouse double minute homolog 2 (p-HDM2) and phosphorylated apoptosis signal regulating kinase 1 (p-ASK1) with concomitant elevation of p53, p21, and phosphorylated p38 MAPK. Forced expression of the active Akt reduced both CSE-induced cytotoxicity and alteration in HDM2/p53/p21 and ASK1/p38 MAPK, compared with the inactive Akt. Of note, CSE induced expression of the tetratricopeptide repeat domain 3 (TTC3), known as a ubiquitin ligase for active Akt. TTC3 siRNAs suppressed not only CSE-induced Akt degradation but also CSE-induced cytotoxicity. Accordingly, rat lungs exposed to cigarette smoke for 3 months showed elevated TTC3 expression and reduced Akt and p-Akt. Taken together, these data suggest that cigarette smoke induces cytotoxicity, partly through Akt degradation via the ubiquitin-proteasome system, in which TTC3 acts as a ubiquitin ligase for active Akt.

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Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells

Cited by 68 publications

References 54 publications

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice

Akt is negatively regulated by the MULAN E3 ligase

Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

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Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells

Cited by 68 publications

References 54 publications

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc Δ716 mice

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc Δ716 mice

Akt is negatively regulated by the MULAN E3 ligase

Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

Contact Info

Product

Resources

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Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice

Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc ^Δ716 mice