title: Activation of murine double minute 2 by Akt in mammary epithelium delays mammary involution and accelerates mammary tumorigenesis.
abstract: Amplification or overexpression of murine double minute 2 (MDM2) promotes a variety of human tumors by degrading tumor suppressor proteins such as p53. Phosphorylation of MDM2 on Ser(166) and Ser(186) by the survival kinase Akt inhibits p53-mediated apoptosis. However, it is unclear whether this pathway contributes to normal or malignant pathophysiology in vivo. To address these questions, we generated transgenic mice expressing the Akt-phosphorylated form of MDM2 (MDM2DDS166D/S186D) in the mammary epithelium. Activation of MDM2 delayed mammary gland involution and accelerated tumor progression in mouse mammary tumor virus/neu transgenic mice by inhibiting apoptosis in a manner associated with decreased p53 expression. Our findings offer in vivo evidence that activation of MDM2 by Akt contributes to mammary development and tumorigenesis.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Cheng
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hsu
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Lang
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Chou
authors.forename: Yi
authors.initials: Y
authors.lastname: Du
authors.forename: Hui-Lung
authors.initials: HL
authors.lastname: Sun
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Wyszomierski
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt