title: Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma.
abstract: The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Verline
authors.initials: V
authors.lastname: Justilien
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Ali
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Jamieson
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Yin
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Adrienne D
authors.initials: AD
authors.lastname: Cox
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Murray
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: fields.alan@mayo.edu.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Fields
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001310:Auranofin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D048749:Cytokinesis; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D008175:Lung Neoplasms / Q000209:etiology*; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D000090243:Nucleophosmin; D011493:Protein Kinase C / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology; D000099293:Protein Kinase C-lambda
chemical_list: D001310:Auranofin; D007527:Isoenzymes; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53; D020830:rac1 GTP-Binding Protein; D000099293:Protein Kinase C-lambda; C489850:ECT2 protein, human; C117307:KRAS protein, human; C000716967:NPM1 protein, human; C107953:RAC1 protein, human; C495901:TP53 protein, human
keywords: Ect2; nucleophosmin, NPM; protein kinase Cι, PKCι; rRNA synthesis; tumor initiation; upstream binding factor 1, UBF1