This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted 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 Kakudo, Y. Articles by Ishioka, C. Search for Related Content PubMed PubMed Citation Articles by Kakudo, Y. Articles by Ishioka, C.

Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Department of Clinical Oncology, Institute of Development, Aging and Cancer, and Tohoku University Hospital, Tohoku University, Sendai, Japan

Requests for reprints: Chikashi Ishioka, Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8542; Fax: 81-22-717-8548; E-mail: chikashi{at}idac.tohoku.ac.jp.

Tumor suppressor p53-dependent apoptosis is thought to be one of the most important tumor-suppressive functions in human tumorigenesis. However, whether the major mechanism underlying the p53-dependent apoptosis is transactivation dependent or independent remains unclear. Using 179 mutant p53s with diverse transcriptional activities for distinct p53-binding sequences in yeast, we evaluated both their sequence-specific transcriptional activities on six p53 target genes and their ability to induce apoptosis in Saos-2 cells. These mutant p53s also represented diversity in their ability to both transactivate target genes and induce apoptosis. We identified 17 mutant p53s with superior ability to induce apoptosis than wild-type p53 that tend to cluster at residues 121 or 290 to 292. There was no significant correlation between the two functional properties on any single target gene examined. Furthermore, the 17 mutant p53s were not classified in a specific cluster by hierarchical cluster analysis on their diverse transcriptional activities, indicating that these mutant p53s were not similar in the transcriptional activity of downstream genes. These results suggested that transactivation-dependent apoptosis does not always play a major role in p53-dependent apoptosis, indirectly supporting the importance role of the transactivation-independent mechanism.

Key Words: p53 • super p53 • transactivation • apoptosis

This article has been cited by other articles:

				E. C. Pietsch, E. Perchiniak, A. A. Canutescu, G. Wang, R. L. Dunbrack, and M. E. Murphy Oligomerization of BAK by p53 Utilizes Conserved Residues of the p53 DNA Binding Domain J. Biol. Chem., July 25, 2008; 283(30): 21294 - 21304. [Abstract] [Full Text] [PDF]

				P. Monti, Y. Ciribilli, J. Jordan, P. Menichini, D. M. Umbach, M. A. Resnick, L. Luzzatto, A. Inga, and G. Fronza Transcriptional Functionality of Germ Line p53 Mutants Influences Cancer Phenotype Clin. Cancer Res., July 1, 2007; 13(13): 3789 - 3795. [Abstract] [Full Text] [PDF]

				C. Stevens, Y. Lin, M. Sanchez, E. Amin, E. Copson, H. White, V. Durston, D. M. Eccles, and T. Hupp A Germ Line Mutation in the Death Domain of DAPK-1 Inactivates ERK-induced Apoptosis J. Biol. Chem., May 4, 2007; 282(18): 13791 - 13803. [Abstract] [Full Text] [PDF]

				F. Vikhanskaya, M. K. Lee, M. Mazzoletti, M. Broggini, and K. Sabapathy Cancer-derived p53 mutants suppress p53-target gene expression--potential mechanism for gain of function of mutant p53 Nucleic Acids Res., March 19, 2007; 35(6): 2093 - 2104. [Abstract] [Full Text] [PDF]

				H. Ohori, H. Yamakoshi, M. Tomizawa, M. Shibuya, Y. Kakudo, A. Takahashi, S. Takahashi, S. Kato, T. Suzuki, C. Ishioka, et al. Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer. Mol. Cancer Ther., October 1, 2006; 5(10): 2563 - 2571. [Abstract] [Full Text] [PDF]

				K. Kojima, M. Konopleva, T. McQueen, S. O'Brien, W. Plunkett, and M. Andreeff Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia Blood, August 1, 2006; 108(3): 993 - 1000. [Abstract] [Full Text] [PDF]

				Y.-J. Chen, V. Hakin-Smith, M. Teo, G. E. Xinarianos, D. A. Jellinek, T. Carroll, D. McDowell, M. R. MacFarlane, R. Boet, B. C. Baguley, et al. Association of Mutant TP53 with Alternative Lengthening of Telomeres and Favorable Prognosis in Glioma. Cancer Res., July 1, 2006; 66(13): 6473 - 6476. [Abstract] [Full Text] [PDF]

				M. Lacroix, R.-A. Toillon, and G. Leclercq p53 and breast cancer, an update. Endocr. Relat. Cancer, June 1, 2006; 13(2): 293 - 325. [Abstract] [Full Text] [PDF]

				B. S. Sayan, A. E. Sayan, R. A. Knight, G. Melino, and G. M. Cohen p53 Is Cleaved by Caspases Generating Fragments Localizing to Mitochondria J. Biol. Chem., May 12, 2006; 281(19): 13566 - 13573. [Abstract] [Full Text] [PDF]

				B. Iacopetta, A. Russo, V. Bazan, G. Dardanoni, N. Gebbia, T. Soussi, D. Kerr, H. Elsaleh, R. Soong, D. Kandioler, et al. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study Ann. Onc., May 1, 2006; 17(5): 842 - 847. [Abstract] [Full Text] [PDF]

				D. Menendez, A. Inga, and M. A. Resnick The Biological Impact of the Human Master Regulator p53 Can Be Altered by Mutations That Change the Spectrum and Expression of Its Target Genes. Mol. Cell. Biol., March 1, 2006; 26(6): 2297 - 2308. [Abstract] [Full Text] [PDF]

				K. Kojima, M. Konopleva, I. J. Samudio, M. Shikami, M. Cabreira-Hansen, T. McQueen, V. Ruvolo, T. Tsao, Z. Zeng, L. T. Vassilev, et al. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy Blood, November 1, 2005; 106(9): 3150 - 3159. [Abstract] [Full Text] [PDF]