title: Cell cycle-controlled interaction of nucleolin with the retinoblastoma protein and cancerous cell transformation.
abstract: Retinoblastoma protein (Rb) is a multifunctional tumor suppressor, frequently inactivated in certain types of human cancer. Nucleolin is an abundant multifunctional phosphoprotein of proliferating and cancerous cells, recently identified as cell cycle-regulated transcription activator, controlling expression of human papillomavirus type 18 (HPV18) oncogenes in cervical cancer. Here we find that nucleolin is associated with Rb in intact cells in the G1 phase of the cell cycle, and the complex formation is mediated by the growth-inhibitory domain of Rb. Association with Rb inhibits the DNA binding function of nucleolin and in consequence the interaction of nucleolin with the HPV18 enhancer, resulting in Rb-mediated repression of the HPV18 oncogenes. The intracellular distribution of nucleolin in epithelial cells is Rb-dependent, and an altered nucleolin localization in human cancerous tissues results from a loss of Rb. Our findings suggest that deregulated nucleolin activity due to a loss of Rb contributes to tumor development in malignant diseases, thus providing further insights into the molecular network for the Rb-mediated tumor suppression.
authors.affiliation: Institute of Transplantation Diagnostics and Cellular Therapeutics, Heinrich Heine University Medical Center, 40225 Düsseldorf, Germany. Electronic address: Edgar.Grinstein@itz.uni-duesseldorf.de.
authors.forename: Edgar
authors.initials: E
authors.lastname: Grinstein
authors.affiliation: Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Institute of Molecular Pharmacology, 13125 Berlin, Germany.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Robert-Rossle-Clinic at the HELIOS Klinikum Berlin-Buch, Charite Medical School, 13125 Berlin, Germany.
authors.forename: Leonid
authors.initials: L
authors.lastname: Karawajew
authors.affiliation: Department of Pathology, Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands.
authors.forename: Peter J F
authors.initials: PJF
authors.lastname: Snijders
authors.affiliation: Department of Pathology, Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands.
authors.forename: Chris J L M
authors.initials: CJLM
authors.lastname: Meijer
authors.affiliation: Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Center for Advanced European Studies, 53175 Bonn, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Royer
authors.affiliation: Institute of Transplantation Diagnostics and Cellular Therapeutics, Heinrich Heine University Medical Center, 40225 Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wernet
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D052161:Human papillomavirus 18 / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097796:Nucleolin
chemical_list: D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D000097796:Nucleolin