title: Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes.
abstract: Aberrant regulation of rRNA synthesis and translation control can facilitate tumorigenesis. The ErbB2 growth factor receptor is overexpressed in many human tumors and has been detected in the nucleus, but the role of nuclear ErbB2 is obscure. In this study, we defined a novel function of nuclear ErbB2 in enhancing rRNA gene transcription by RNA polymerase-I (RNA Pol I). Nuclear ErbB2 physically associates with β-actin and RNA Pol I, coinciding with active RNA Pol I transcription sites in nucleoli. RNA interference-mediated knockdown of ErbB2 reduced pre-rRNA and protein synthesis. In contrast, wild-type ErbB2 augmented pre-rRNA level, protein production, and cell size/cell growth, but not by an ErbB2 mutant that is defective in nuclear translocation. Chromatin immunoprecipitation assays revealed that ErbB2 enhances binding of RNA Pol I to rDNA. In addition, ErbB2 associated with rDNA, RNA Pol I, and β-actin, suggesting how it could stimulate rRNA production, protein synthesis, and increased cell size and cell growth. Finally, ErbB2-potentiated RNA Pol I transcription could be stimulated by ligand and was not substantially repressed by inhibition of PI3-K and MEK/ERK (extracellular signal regulated kinase), the main ErbB2 effector signaling pathways. Together, our findings indicate that nuclear ErbB2 functions as a regulator of rRNA synthesis and cellular translation, which may contribute to tumor development and progression.
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. lyl@mail.cmu.edu.tw
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Hsiuyi
authors.initials: H
authors.lastname: Chen
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Hsieh
authors.forename: Ying-Nai
authors.initials: YN
authors.lastname: Wang
authors.forename: Hsiao-Ju
authors.initials: HJ
authors.lastname: Chu
authors.forename: Ya-Huey
authors.initials: YH
authors.lastname: Chen
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Chen
authors.forename: Peng-Ju
authors.initials: PJ
authors.lastname: Chien
authors.forename: Haou-Tzong
authors.initials: HT
authors.lastname: Ma
authors.forename: Ho-Cheng
authors.initials: HC
authors.lastname: Tsai
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.forename: Yuh-Pyng
authors.initials: YP
authors.lastname: Sher
authors.forename: Huang-Chun
authors.initials: HC
authors.lastname: Lien
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Tsai
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000199:Actins / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048429:Cell Size; D004275:DNA, Ribosomal / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D020459:Genes, rRNA; D006801:Humans; D009369:Neoplasms / Q000209:etiology*; D014176:Protein Biosynthesis; D012318:RNA Polymerase I / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D000199:Actins; D004275:DNA, Ribosomal; D048049:Extracellular Signal-Regulated MAP Kinases; D012318:RNA Polymerase I; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human