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J. Biol. Chem., Vol. 281, Issue 31, 22223-22235, August 4, 2006

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Cell Cycle-controlled Interaction of Nucleolin with the Retinoblastoma Protein and Cancerous Cell Transformation^*

Edgar Grinstein¹, Ying Shan^¶, Leonid Karawajew^||, Peter J. F. Snijders^**, Chris J. L. M. Meijer^**, Hans-Dieter Royer, and Peter Wernet

From the Institute of Transplantation Diagnostics and Cellular Therapeutics, Heinrich Heine University Medical Center, 40225 Düsseldorf, Germany, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany, ^¶Institute of Molecular Pharmacology, 13125 Berlin, Germany, ^||Robert-Rossle-Clinic at the HELIOS Klinikum Berlin-Buch, Charite Medical School, 13125 Berlin, Germany, the ^**Department of Pathology, Vrije Universiteit Medical Center, 1007 MB Amsterdam, The Netherlands, and Center for Advanced European Studies, 53175 Bonn, Germany

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.

Received for publication, December 15, 2005 , and in revised form, May 11, 2006.

^* This work was supported by research grants from the Research Commission of the Medical Faculty of the University of Düsseldorf and the Ministry of Innovation, Science, Research, and Technology of the State of North Rhine Westphalia (to E. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Institute of Transplantation Diagnostics and Cellular Therapeutics, Heinrich Heine University Medical Center, Moorenstr. 5, Bldg. 14.80, 40225 Düsseldorf, Germany. Tel.: 49-211-811-9534; Fax: 49-211-811-9147; E-mail: Edgar.Grinstein{at}itz.uni-duesseldorf.de.

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