title: K-Ras stabilization by estrogen via PKCδ is involved in endometrial tumorigenesis.
abstract: Estrogens are considered as a major risk factor of endometrial cancer. In this study, we identified a mechanism of tumorigenesis in which K-Ras protein is stabilized via estrogen signaling through the ER-α36 receptor. PKCδ was shown to stabilize K-Ras specifically via estrogen signaling. Estrogens stabilize K-Ras via inhibition of polyubiquitylation-dependent proteasomal degradation. Estrogen-induced cellular transformation was abolished by either K-Ras or PKCδ knockdown. The role of PKCδ in estrogen-induced tumorigenesis was confirmed in a mouse xenograft model by reduction of tumors after treatment with rottlerin, a PKCδ inhibitor. Finally, levels of PKCδ correlated with that of Ras in human endometrial tumor tissues. Stabilization of K-Ras by estrogen signaling involving PKCδ up-regulation provides a potential therapeutic approach for treatment of endometrial cancer.
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Kyoung-Hwa
authors.initials: KH
authors.lastname: Koo
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Woo-Jeong
authors.initials: WJ
authors.lastname: Jeong
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Cho
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Jong-Chan
authors.initials: JC
authors.lastname: Park
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea.
authors.forename: Do Sik
authors.initials: do S
authors.lastname: Min
authors.affiliation: Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.|Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003513:Cycloheximide / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004967:Estrogens; D011960:Receptors, Estrogen; D003513:Cycloheximide; C497259:Prkcd protein, mouse; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins
keywords: K-Ras; PKCδ; endometrial cancer; estrogen; tumorigenesis