This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Petrenko, O.
Right arrow Articles by Moll, U. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Petrenko, O.
Right arrow Articles by Moll, U. M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2003, p. 5540-5555, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5540-5555.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

{Delta}Np73 Facilitates Cell Immortalization and Cooperates with Oncogenic Ras in Cellular Transformation In Vivo

Oleksi Petrenko,1 Alexander Zaika,1,2 and Ute M. Moll1*

Department of Pathology, Stony Brook University, Stony Brook, New York 11794,1 Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia 229082

Received 29 January 2003/ Returned for modification 20 March 2003/ Accepted 20 May 2003

TP73, despite significant homology to TP53, is not a classic tumor suppressor gene, since it exhibits upregulation of nonmutated products in human tumors and lacks a tumor phenotype in p73-deficient mice. We recently reported that an N-terminally truncated isoform, {Delta}Np73, is upregulated in breast and gynecological cancers. We further showed that {Delta}Np73 is a potent transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells by efficiently counteracting their target gene transactivations, apoptosis, and growth suppression functions (A. I. Zaika et al., J. Exp. Med. 6:765-780, 2002). Although these data strongly suggest oncogenic properties of {Delta}Np73, this can only be directly shown in primary cells. We report here that {Delta}Np73 confers resistance to spontaneous replicative senescence of primary mouse embryo fibroblasts (MEFs) and immortalizes MEFs at a 1,000-fold-higher frequency than occurs spontaneously. {Delta}Np73 cooperates with cMyc and E1A in promoting primary cell proliferation and colony formation and compromises p53-dependent MEF apoptosis. Importantly, {Delta}Np73 rescues Ras-induced senescence. Moreover, {Delta}Np73 cooperates with oncogenic Ras in transforming primary fibroblasts in vitro and in inducing MEF-derived fibrosarcomas in vivo in nude mice. Wild-type p53 is likely a major target of {Delta}Np73 inhibition in primary fibroblasts since deletion of p53 or its requisite upstream activator ARF abrogates the growth-promoting effect of {Delta}Np73. Taken together, {Delta}Np73 behaves as an oncogene that targets p53 that might explain why {Delta}Np73 upregulation may be selected for during tumorigenesis of human cancers.

* Corresponding author. Mailing address: Department of Pathology, Stony Brook University, Stony Brook, NY 11794-8691. Phone: (631) 444-2459. Fax: (631) 444-3424. E-mail: umoll{at}notes.cc.sunysb.edu.

Molecular and Cellular Biology, August 2003, p. 5540-5555, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5540-5555.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Marques-Garcia, F., Ferrandiz, N., Fernandez-Alonso, R., Gonzalez-Cano, L., Herreros-Villanueva, M., Rosa-Garrido, M., Fernandez-Garcia, B., Vaque, J. P., Marques, M. M., Alonso, M. E., Segovia, J. C., Leon, J., Marin, M. C. (2009). p73 Plays a Role in Erythroid Differentiation through GATA1 Induction. J. Biol. Chem. 284: 21139-21156 [Abstract] [Full Text]  
  • Roperch, J.-P., El Ouadrani, K., Hendrix, A., Emami, S., De Wever, O., Melino, G., Gespach, C. (2008). Netrin-1 Induces Apoptosis in Human Cervical Tumor Cells via the TAp73{alpha} Tumor Suppressor. Cancer Res. 68: 8231-8239 [Abstract] [Full Text]  
  • Tannapfel, A., John, K., Mise, N., Schmidt, A., Buhlmann, S., Ibrahim, S. M., Putzer, B. M. (2008). Autonomous growth and hepatocarcinogenesis in transgenic mice expressing the p53 family inhibitor DNp73. Carcinogenesis 29: 211-218 [Abstract] [Full Text]  
  • Zhang, J., Chen, X. (2007). {Delta}Np73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA. Mol. Cell. Biol. 27: 3868-3880 [Abstract] [Full Text]  
  • Mondal, A. M., Chinnadurai, S., Datta, K., Chauhan, S. S., Sinha, S., Chattopadhyay, P. (2006). Identification and Functional Characterization of a Novel Unspliced Transcript Variant of HIC-1 in Human Cancer Cells Exposed to Adverse Growth Conditions. Cancer Res. 66: 10466-10477 [Abstract] [Full Text]  
  • Lunghi, P., Costanzo, A., Salvatore, L., Noguera, N., Mazzera, L., Tabilio, A., Lo-Coco, F., Levrero, M., Bonati, A. (2006). MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis. Blood 107: 4549-4553 [Abstract] [Full Text]  
  • Dominguez, G., Garcia, J. M., Pena, C., Silva, J., Garcia, V., Martinez, L., Maximiano, C., Gomez, M. E., Rivera, J. A., Garcia-Andrade, C., Bonilla, F. (2006). {Delta}TAp73 Upregulation Correlates With Poor Prognosis in Human Tumors: Putative In Vivo Network Involving p73 Isoforms, p53, and E2F-1. JCO 24: 805-815 [Abstract] [Full Text]  
  • Malaguarnera, R., Mandarino, A., Mazzon, E., Vella, V., Gangemi, P., Vancheri, C., Vigneri, P., Aloisi, A., Vigneri, R., Frasca, F. (2005). The p53-homologue p63 may promote thyroid cancer progression. Endocr Relat Cancer 12: 953-971 [Abstract] [Full Text]  
  • Nyman, U., Sobczak-Pluta, A., Vlachos, P., Perlmann, T., Zhivotovsky, B., Joseph, B. (2005). Full-length p73{alpha} Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells. J. Biol. Chem. 280: 34159-34169 [Abstract] [Full Text]  
  • Tomkova, K., Belkhiri, A., El-Rifai, W., Zaika, A. I. (2004). p73 Isoforms Can Induce T-Cell Factor-Dependent Transcription in Gastrointestinal Cells. Cancer Res. 64: 6390-6393 [Abstract] [Full Text]  
  • Moll, U. M., Slade, N. (2004). p63 and p73: Roles in Development and Tumor Formation. Mol Cancer Res 2: 371-386 [Abstract] [Full Text]  
  • Concin, N., Becker, K., Slade, N., Erster, S., Mueller-Holzner, E., Ulmer, H., Daxenbichler, G., Zeimet, A., Zeillinger, R., Marth, C., Moll, U. M. (2004). Transdominant {Delta}TAp73 Isoforms Are Frequently Up-regulated in Ovarian Cancer. Evidence for Their Role as Epigenetic p53 Inhibitors in Vivo. Cancer Res. 64: 2449-2460 [Abstract] [Full Text]  
  • Moll, U. M. (2003). The Role of p63 and p73 in Tumor Formation and Progression: Coming of Age Toward Clinical Usefulness: Commentary re: F. Koga et al., Impaired p63 Expression Associates with Poor Prognosis and Uroplakin III Expression in Invasive Urothelial Carcinoma of the Bladder. Clin. Cancer Res., 9: 5501-5507, 2003, and P. Puig et al., p73 Expression in Human Normal and Tumor Tissues: Loss of p73{alpha} Expression Is Associated with Tumor Progression in Bladder Cancer. Clin. Cancer Res., 9: 5642-5651, 2003.. Clin. Cancer Res. 9: 5437-5441 [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»