Browsing by Author "Kadakia, Madhavi P."

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    Pten loss induces autocrine FGF signaling to promote skin tumorigenesis
    (Elsevier, 2014) Hertzler-Schaefer, Kristina; Mathew, Grinu; Somani, Ally-Khan; Tholpady, Sunil; Kadakia, Madhavi P.; Chen, Yiping; Spandau, Dan F.; Zhang, Xin; Dermatology, School of Medicine
    Inactivation of the Pten tumor suppressor negatively regulates the PI3K-mTOR pathway. In a model of cutaneous squamous cell carcinoma (SCC), we demonstrate that deletion of Pten strongly elevates Fgf10 protein levels without increasing Fgf10 transcription in vitro and in vivo. The translational activation of Fgf10 by Pten deletion is reversed by genetic disruption of the mTORC1 complex, which also prevents skin tumorigenesis in Pten mutants. We further show that ectopic expression of Fgf10 causes skin papillomas, whereas Pten deletion-induced skin tumors are inhibited by epidermal deletion of Fgfr2. Collectively, our data identify autocrine activation of FGF signaling as an essential mechanism in promoting Pten-deficient skin tumors.
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    Serdemetan Antagonizes the Mdm2-HIF1α Axis Leading to Decreased Levels of Glycolytic Enzymes
    (Public Library of Science, 2013-09-06) Lehman, Jason A.; Hauck, Paula M.; Gendron, Jaimie M.; Batuello, Christopher N.; Eitel, Jacob A.; Albig, Allan; Kadakia, Madhavi P.; Mayo, Lindsey D.; Pediatrics, School of Medicine
    Serdemetan (JNJ-26854165), an antagonist to Mdm2, was anticipated to promote the activation of p53. While regulation of p53 by Mdm2 is important, Mdm2 also regulates numerous proteins involved in diverse cellular functions. We investigated if Serdemetan would alter the Mdm2-HIF1α axis and affect cell survival in human glioblastoma cells independently of p53. Treatment of cells with Serdemetan under hypoxia resulted in a decrease in HIF1α levels. HIF1α downstream targets, VEGF and the glycolytic enzymes (enolase, phosphoglycerate kinase1/2, and glucose transporter 1), were all decreased in response to Serdemetan. The involvement of Mdm2 in regulating gene expression of glycolytic enzymes raises the possibility of side effects associated with therapeutically targeting Mdm2.