This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hsiao, M. Articles by Haas, M. Search for Related Content PubMed PubMed Citation Articles by Hsiao, M. Articles by Haas, M.

American Journal of Pathology, Vol 145, 702-714, Copyright © 1994 by American Society for Investigative Pathology

REGULAR ARTICLES

Gain-of-function mutations of the p53 gene induce lymphohematopoietic metastatic potential and tissue invasiveness

M Hsiao, J Low, E Dorn, D Ku, P Pattengale, J Yeargin and M Haas
Department of Biology/Cancer Center, University of California, San Diego, La Jolla.

Leukemia cell infiltration and the induction of lethal hematopoietic disease in immune-deficient SCID mice transplanted with human T cell acute lymphoblastic T leukemia (T-ALL) cells occurred only when the cells possessed mutant p53 genes and lacked a wild-type allele or when T-ALL cells lacking p53 protein were infected with specific mutant p53 genes. A series of six mutant p53 genes were cloned from relapse T-ALL- derived cell lines and were constructed into defective retroviral expression vectors. Viruses encoding mutant p53 proteins were used to infect relapse T-ALL cells in a study designed to compare their pathogenic potency. The mutant p53 genes possessed a distinct hierarchy in vivo and in vitro: mutants inducing the greatest increase in proliferation of different T-ALL lines in vitro and colony formation in methylcellulose cultures also induced tissue invasiveness of infected T- ALL cells in vivo. Mutant p53 gene transfer to a cell line lacking p53 protein showed that the more potent p53 mutants possessed a distinctive dominant oncogenic activity in vitro and in vivo. The dominant oncogenic activity of these mutant p53 proteins was not dependent on the presence of and on complex formation with wild-type p53 protein. These "hot" p53 mutations thus represent bona fide gain-of-function mutations. Infection of p53-negative T-ALL cells with viruses encoding gain-of-function mutant p53 genes resulted in the acquisition of metastatic potential and tissue invasiveness. Taken together, our results suggest that specific mutant p53 genes play a role in the generation of lymphohematopoietic metastatic potential and tissue invasiveness as assayed in SCID mice, whereas the expression of wild- type p53 is capable of keeping this metastatic potential in check.

This article has been cited by other articles:

				T.-H. Kim, S. Y. Lee, J. H. Rho, N. Y. Jeong, Y. H. Soung, W. S. Jo, D.-Y. Kang, S.-H. Kim, and Y. H. Yoo Mutant p53 (G199V) Gains Antiapoptotic Function through Signal Transducer and Activator of Transcription 3 in Anaplastic Thyroid Cancer Cells Mol. Cancer Res., October 1, 2009; 7(10): 1645 - 1654. [Abstract] [Full Text] [PDF]

				T. Bihani, A. Chicas, C. P.-K. Lo, and A. W. Lin Dissecting the Senescence-like Program in Tumor Cells Activated by Ras Signaling J. Biol. Chem., January 26, 2007; 282(4): 2666 - 2675. [Abstract] [Full Text] [PDF]

				M. J. Scian, K. E. R. Stagliano, M. A. E. Anderson, S. Hassan, M. Bowman, M. F. Miles, S. P. Deb, and S. Deb Tumor-Derived p53 Mutants Induce NF-{kappa}B2 Gene Expression Mol. Cell. Biol., November 15, 2005; 25(22): 10097 - 10110. [Abstract] [Full Text] [PDF]

				J. S. Wunder, N. Gokgoz, R. Parkes, S. B. Bull, S. Eskandarian, A. M. Davis, C. P. Beauchamp, E. U. Conrad, R. J. Grimer, J. H. Healey, et al. TP53 Mutations and Outcome in Osteosarcoma: A Prospective, Multicenter Study J. Clin. Oncol., March 1, 2005; 23(7): 1483 - 1490. [Abstract] [Full Text] [PDF]

				T. J. O'Farrell, P. Ghosh, N. Dobashi, C. Y. Sasaki, and D. L. Longo Comparison of the Effect of Mutant and Wild-Type p53 on Global Gene Expression Cancer Res., November 15, 2004; 64(22): 8199 - 8207. [Abstract] [Full Text] [PDF]

				L. Weisz, A. Zalcenstein, P. Stambolsky, Y. Cohen, N. Goldfinger, M. Oren, and V. Rotter Transactivation of the EGR1 Gene Contributes to Mutant p53 Gain of Function Cancer Res., November 15, 2004; 64(22): 8318 - 8327. [Abstract] [Full Text] [PDF]

				S. Pospisilova, C. Siligan, J. Ban, G. Jug, and H. Kovar Constitutive and DNA Damage Inducible Activation of pig3 and MDM2 Genes by Tumor-Derived p53 Mutant C277Y Mol. Cancer Res., May 1, 2004; 2(5): 296 - 304. [Abstract] [Full Text] [PDF]

				S. L. Rose, A. D. Robertson, M. J. Goodheart, B. J. Smith, B. R. DeYoung, and R. E. Buller The Impact of p53 Protein Core Domain Structural Alteration on Ovarian Cancer Survival Clin. Cancer Res., September 15, 2003; 9(11): 4139 - 4144. [Abstract] [Full Text] [PDF]

				K. V. Gurova, O. W. Rokhlin, A. V. Budanov, L. G. Burdelya, P. M. Chumakov, M. B. Cohen, and A. V. Gudkov Cooperation of Two Mutant p53 Alleles Contributes to Fas Resistance of Prostate Carcinoma Cells Cancer Res., June 1, 2003; 63(11): 2905 - 2912. [Abstract] [Full Text] [PDF]

				Y. Ohiro, A. Usheva, S. Kobayashi, S. L. Duffy, R. Nantz, D. Gius, and N. Horikoshi Inhibition of Stress-Inducible Kinase Pathways by Tumorigenic Mutant p53 Mol. Cell. Biol., January 1, 2003; 23(1): 322 - 334. [Abstract] [Full Text]

				Z. Zhang, J. Li, L. E. Lantry, Y. Wang, R. W. Wiseman, R. A. Lubet, and M. You p53 Transgenic Mice Are Highly Susceptible to 1, 2-Dimethylhydrazine-induced Uterine Sarcomas Cancer Res., June 1, 2002; 62(11): 3024 - 3029. [Abstract] [Full Text] [PDF]

				S. El-Hizawi, J. P. Lagowski, M. Kulesz-Martin, and A. Albor Induction of Gene Amplification as a Gain-of-Function Phenotype of Mutant p53 Proteins Cancer Res., June 1, 2002; 62(11): 3264 - 3270. [Abstract] [Full Text] [PDF]

				S. Strano, G. Fontemaggi, A. Costanzo, M. G. Rizzo, O. Monti, A. Baccarini, G. Del Sal, M. Levrero, A. Sacchi, M. Oren, et al. Physical Interaction with Human Tumor-derived p53 Mutants Inhibits p63 Activities J. Biol. Chem., May 17, 2002; 277(21): 18817 - 18826. [Abstract] [Full Text] [PDF]

				A. Yuan, C.-J. Yu, K.-T. Luh, S.-H. Kuo, Y.-C. Lee, and P.-C. Yang Aberrant p53 Expression Correlates With Expression of Vascular Endothelial Growth Factor mRNA and Interleukin-8 mRNA and Neoangiogenesis in Non-Small-Cell Lung Cancer J. Clin. Oncol., February 15, 2002; 20(4): 900 - 910. [Abstract] [Full Text] [PDF]

				J. A. Cerrato, W.K. A. Yung, and T.-J. Liu Introduction of mutant p53 into a wild-type p53-expressing glioma cell line confers sensitivity to Ad-p53-induced apoptosis Neuro-oncol, April 1, 2001; 3(2): 113 - 122. [Abstract] [PDF]

				A. Sigal and V. Rotter Oncogenic Mutations of the p53 Tumor Suppressor: The Demons of the Guardian of the Genome Cancer Res., December 1, 2000; 60(24): 6788 - 6793. [Abstract] [Full Text]

				M. G. C. T. van Oijen and P. J. Slootweg Gain-of-Function Mutations in the Tumor Suppressor Gene p53 Clin. Cancer Res., June 1, 2000; 6(6): 2138 - 2145. [Abstract] [Full Text]

				A. Cabelguenne, H. Blons, I. de Waziers, F. Carnot, A.-M. Houllier, T. Soussi, D. Brasnu, P. Beaune, O. Laccourreye, and P. Laurent-Puig p53 Alterations Predict Tumor Response to Neoadjuvant Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Prospective Series J. Clin. Oncol., April 7, 2000; 18(7): 1465 - 1473. [Abstract] [Full Text] [PDF]

				S. Kubicka, F. Kuhnel, L. Zender, K. L. Rudolph, J. Plumpe, M. Manns, and C. Trautwein p53 Represses CAAT Enhancer-binding Protein (C/EBP)-dependent Transcription of the Albumin Gene. A MOLECULAR MECHANISM INVOLVED IN VIRAL LIVER INFECTION WITH IMPLICATIONS FOR HEPATOCARCINOGENESIS J. Biol. Chem., November 5, 1999; 274(45): 32137 - 32144. [Abstract] [Full Text] [PDF]

				S.-K. Lee, H.-J. Kim, J. W. Kim, and J. W. Lee Steroid Receptor Coactivator-1 and Its Family Members Differentially Regulate Transactivation by the Tumor Suppressor Protein p53 Mol. Endocrinol., November 1, 1999; 13(11): 1924 - 1933. [Abstract] [Full Text]

				K. Will, G. Warnecke, L. Wiesmuller, and W. Deppert Specific interaction of mutant p53 with regions of matrix attachment region DNA elements (MARs) with a high potential for base-unpairing PNAS, November 10, 1998; 95(23): 13681 - 13686. [Abstract] [Full Text] [PDF]

				M. L. Hixon, A. I. Flores, M. W. Wagner, and A. Gualberto Ectopic Expression of cdc2/cdc28 Kinase Subunit Homo sapiens 1 Uncouples Cyclin B Metabolism from the Mitotic Spindle Cell Cycle Checkpoint Mol. Cell. Biol., November 1, 1998; 18(11): 6224 - 6237. [Abstract] [Full Text]

				M. W. Frazier, X. He, J. Wang, Z. Gu, J. L. Cleveland, and G. P. Zambetti Activation of c-myc Gene Expression by Tumor-Derived p53 Mutants Requires a Discrete C-Terminal Domain Mol. Cell. Biol., July 1, 1998; 18(7): 3735 - 3743. [Abstract] [Full Text]

				A. Gualberto, K. Aldape, K. Kozakiewicz, and T. D. Tlsty An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control PNAS, April 28, 1998; 95(9): 5166 - 5171. [Abstract] [Full Text] [PDF]

				F. M. Uckun, M. G. Sensel, L. Sun, P. G. Steinherz, M. E. Trigg, N. A. Heerema, H. N. Sather, G. H. Reaman, and P. S. Gaynon Biology and Treatment of Childhood T-Lineage Acute Lymphoblastic Leukemia Blood, February 1, 1998; 91(3): 735 - 746. [Full Text] [PDF]

				L J Ko and C Prives p53: puzzle and paradigm. Genes & Dev., May 1, 1996; 10(9): 1054 - 1072. [PDF]

				Y. Peng, L. Chen, C. Li, W. Lu, S. Agrawal, and J. Chen Stabilization of the MDM2 Oncoprotein by Mutant p53 J. Biol. Chem., February 23, 2001; 276(9): 6874 - 6878. [Abstract] [Full Text] [PDF]

				Y. Peng, L. Chen, C. Li, W. Lu, and J. Chen Inhibition of MDM2 by hsp90 Contributes to Mutant p53 Stabilization J. Biol. Chem., October 26, 2001; 276(44): 40583 - 40590. [Abstract] [Full Text] [PDF]