Cell cycle-controlled interaction of nucleolin with the retinoblastoma protein and cancerous cell transformation.
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.
Grinstein
Edgar
E
Institute of Transplantation Diagnostics and Cellular Therapeutics, Heinrich Heine University Medical Center, 40225 Düsseldorf, Germany. Electronic address: Edgar.Grinstein@itz.uni-duesseldorf.de.
Shan
Ying
Y
Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Institute of Molecular Pharmacology, 13125 Berlin, Germany.
Karawajew
Leonid
L
Robert-Rossle-Clinic at the HELIOS Klinikum Berlin-Buch, Charite Medical School, 13125 Berlin, Germany.
Snijders
Peter J F
PJF
Department of Pathology, Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands.
Meijer
Chris J L M
CJLM
Department of Pathology, Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands.
Royer
Hans-Dieter
HD
Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Center for Advanced European Studies, 53175 Bonn, Germany.
Wernet
Peter
P
Institute of Transplantation Diagnostics and Cellular Therapeutics, Heinrich Heine University Medical Center, 40225 Düsseldorf, Germany.
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
D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D000097796:Nucleolin