title: ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.
abstract: The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that Erk downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the non-phosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK and MDM2.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
authors.forename: Cong S
authors.initials: CS
authors.lastname: Zong
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ding
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xie
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Lang
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Chang
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Huang
authors.forename: Hsin
authors.initials: H
authors.lastname: Huang
authors.forename: Hsu-Ping
authors.initials: HP
authors.lastname: Kuo
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Huang-Chun
authors.initials: HC
authors.lastname: Lien
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Cheng
authors.forename: King-Jen
authors.initials: KJ
authors.lastname: Chang
authors.forename: Chwan-Deng
authors.initials: CD
authors.lastname: Hsiao
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Tsai
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D012694:Serine; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D048049:Extracellular Signal-Regulated MAP Kinases