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dc.contributor.authorJham, Bruno C.
dc.contributor.authorMa, Tao
dc.contributor.authorHu, Jiadi
dc.contributor.authorChaisuparat, Risa
dc.contributor.authorFriedman, Eitan R.
dc.contributor.authorPandolfi, Pier Paolo
dc.contributor.authorSchneider, Abraham
dc.contributor.authorSodhi, Akrit
dc.contributor.authorMontaner, Silvia
dc.date.accessioned2012-01-03T19:58:49Z
dc.date.issued2011
dc.identifier.citationJham, Bruno C., Tao Ma, Jiadi Hu, Risa Chaisuparat, Eitan R. Friedman, Pier Paolo Pandolfi, Abraham Schneider, Akrit Sodhi, and Silvia Montaner. 2011. Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi's sarcoma. PLoS ONE 6(4): e19103.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:6106395
dc.description.abstractBackground: Kaposi’s sarcoma (KS) is a vascular neoplasm characterized by the dysregulated expression of angiogenic and inflammatory cytokines. The driving force of the KS lesion, the KSHV-infected spindle cell, secretes elevated levels of vascular endothelial growth factor (VEGF), essential for KS development. However, the origin of VEGF in this tumor remains unclear. Methodology/Principal Findings: Here we report that the KSHV G protein-coupled receptor (vGPCR) upregulates VEGF in KS through an intricate paracrine mechanism. The cytokines secreted by the few vGPCR-expressing tumor cells activate in neighboring cells multiple pathways (including AKT, ERK, p38 and IKK\(\beta\)) that, in turn, converge on TSC1/2, promoting mTOR activation, HIF upregulation, and VEGF secretion. Conditioned media from vGPCR-expressing cells lead to an mTORdependent increase in HIF-1\(\alpha\) and HIF-2\(\alpha\) protein levels and VEGF upregulation. In a mouse allograft model for KS, specific inhibition of the paracrine activation of mTOR in non-vGPCR-expressing cells was sufficient to inhibit HIF upregulation in these cells, and abolished the ability of the vGPCR-expressing cells to promote tumor formation \(in\) \(vivo\). Similarly, pharmacologic inhibition of HIF in this model blocked VEGF secretion and also lead to tumor regression. Conclusions/Significance: Our findings provide a compelling explanation for how the few tumor cells expressing vGPCR can contribute to the dramatic amplification of VEGF secretion in KS, and further provide a molecular mechanism for how cytokine dysregulation in KS fuels angiogenesis and tumor development. These data further suggest that activation of HIF by vGPCR may be a vulnerable target for the treatment of patients with KS.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0019103en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084756/pdf/en_US
dash.licenseLAA
dc.subjectAIDS-related cancersen_US
dc.subjectbiologyen_US
dc.subjectmolecular cell biologyen_US
dc.subjectsignal transductionen_US
dc.subjectsignaling in selected disciplinesen_US
dc.subjectKaposi sarcomaen_US
dc.subjectoncogenic signalingen_US
dc.subjectbone and soft tissue sarcomasen_US
dc.subjectsignaling cascadesen_US
dc.subjectsignaling pathwaysen_US
dc.subjectgene expressionen_US
dc.subjectcancers and neoplasmsen_US
dc.subjectmedicineen_US
dc.subjectoncologyen_US
dc.subjectbasic cancer researchen_US
dc.subjecttumor physiologyen_US
dc.titleAmplification of the Angiogenic Signal through the Activation of the TSC/mTOR/HIF Axis by the KSHV vGPCR in Kaposi's Sarcomaen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorPandolfi, Pier Paolo
dc.date.available2012-01-03T19:58:49Z
dash.affiliation.otherHMS^Medicine- Beth Israel-Deaconessen_US
dc.identifier.doi10.1371/journal.pone.0019103*
dash.contributor.affiliatedPandolfi, Pier Paolo


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