The Endoplasmic Reticulum Udpase ENTPD5 Promotes Cancer Cell Growth and Survival in the PI3K/PTEN

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dc.contributor.advisorWang, Xiaodongen
dc.creatorShen, Zhirongen
dc.date.accessioned2011-02-01T19:32:25Z
dc.date.available2011-02-01T19:32:25Z
dc.date.issued2011-02-01
dc.description.abstractPI3 Kinase and PTEN lipid phosphatase control the level of cellular phosphatidylinositol (3,4,5)-trisphosphate, an activator of AKT kinase that promotes cell growth and survival. Mutations activating AKT are commonly observed in human cancers. Activation of AKT and downstream PI3 Kinase signaling promotes protein translation, resulting in increased protein flux into ER; this will lead to decreased efficiency of protein folding and accumulation of unfolded proteins in the ER and finally lead to ER stress. How does cancer cell solve this problem of increased folding during rapid growth to avoid ER stress? We discovered that ENTPD5, an endoplasmic reticulum (ER) enzyme, is up-regulated in cell lines and primary human tumor samples with active AKT. AKT upregulates ENTPD5 by relieving transcriptional inhibition by FoxO transcription factors. ENTPD5 hydrolyzes UDP to UMP to promote protein N-glycosylation and folding in ER. Knockdown of ENTPD5 in PTEN-null cells causes ER stress and loss of receptor tyrosine kinases through ER-associated degradation pathway under stress conditions. Consequently, the growth of PTEN-null cells is inhibited both in vitro and in mouse xenograft tumor models. ENTPD5 is therefore an essential component for PI3K/AKT active cancer cells and a potential drug target for anti-cancer therapy.en
dc.identifier.oclc719445751
dc.identifier.urihttps://hdl.handle.net/2152.5/835
dc.language.isoenen
dc.subjectEndoplasmic Reticulumen
dc.subjectOncogene Proteinsen
dc.subjectCell Proliferationen
dc.titleThe Endoplasmic Reticulum Udpase ENTPD5 Promotes Cancer Cell Growth and Survival in the PI3K/PTENen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2013-01-26
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineIntegrative Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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