The p53 Tumor Suppressor Pathway and Cancer (Protein Reviews Volume 2)

The p53 tumor suppressor gene is mutated in approximately half of all human malignancies, including colon, lung, and breast cancers. It is well recognized that these mutations directly inactivate p53 tumor suppressor function. Furthermore, the p53 protein operates within a pathway and this pathway, including the mutations in p53, is likely inactivated by nearly every human tumor. In support of this hypothesis, 100% of mice that have been engineered such that they do not express p53 protein (knockout animals), develop highly malignant tumors by only 3-6 months of age. The importance of p53 in preventing human cancer is also evident by families in which a mutated p53 gene is inherited from a parent. Individuals who carry an inherited germline p53 mutation are associated with Li-Fraumeni syndrome. These carriers often develop cancer as children or young adults (some have multiple tumors) and remarkably, 90% of these individuals will develop cancer by 60 years of age. Lastly, cigarette smoke, sexually transmitted viruses, and other environmental hazards play a significant role in the disruption of the p53 pathway. The p53 Tumor Suppressor Pathway and Cancer provides a comprehensive review of the p53 tumor suppressor pathway, how p53 functions to prevent tumor genesis, and how this pathway is corrupted during tumor development. The latest, state-of-the-art strategies to combat cancer by targeting p53 defects in tumors is also presented. The current year (2004) marks the Silver Anniversary of the discovery of the p53 tumor suppressor. The emerging ?eld ?rst considered p53 as a viral antigen and then as an oncogene that cooperates with activated ras in transforming primary cells in culture. Fueling the concept of p53 acting as a transforming factor, p53 expression was markedly elevated in various transformed and tumorigenic cell lines when compared to normal cells. In a simple twist of fate, most of the studies conducted in those early years inadvertently relied on a point mutant of p53 that had been cloned from a normal mouse genomic library. A bona ?de wild-type p53 cDNA was subsequently isolated, ironically, from a mouse teratocarcinoma cell line. A decade after its discovery, p53 was shown to be a tumor suppressor that protects against cancer. It is now recognized that approximately half of all human tumors arise due to mutations within the p53 gene. As remarkable as this number may seem, it signi?cantly underrepresents how often the p53 pathway is targeted during tumorigenesis. It is my personal view, as well as many in the p53 ?eld, that the p53-signaling pathway is corrupted in nearly 100% of tumors. If you are interested in understanding cancer and how it develops, you must begin by studying p53 and its pathway. After demonstrating that p53 functions as a tumor suppressor the ?eld exploded and p53 became a major focus of scientists around the world. Ch. 1. The P53 Network / Arnold J. Levine, Jill Bargonetti, Gareth L. Bond, Josephine Hoh, Kenan Onel, Michael Overholtzer, Archontoula Stoffel, Angelica K. Teresky, Christine A. Walsh And Shengkan Jin -- Chapter 2. The Three-dimensional Structure Of P53 / Elena S. Stavridi, Yentram Huyen, Emily A. Sheston And Thanos D. Halazonetis -- Chapter 3. Transcriptional Activation By P53 : Mechanisms And Targeted Genes / Timothy Maclachlan And Wafik El-deiry -- Chapter 4. Transcriptional Repression By The P53 Tumor Suppressor Protein / Jack T. Zilfou And Maureen E. Murphy -- Chapter 5. Posttranslational Modifications Of P53 : Upstream Signaling Pathways / Carl W. Anderson And Ettore Appella -- Chapter 6. P53 In Human Cancer -- Somatic And Inherited Mutations And Mutation-independent Mechanisms / Ute M. Moll And Nicole Concin -- Chapter 7. Mdm2 And Mdmx Regulators Of P53 Activity / Jamil Momand, Paul Joseph Aspuria And Saori Furuta -- Chapter 8. P53 Family Members : P63 And P73 / Elsa R. Flores And Tyler Jacks -- Chapter 9. The Oncogenic Activity Of P53 Mutants / Alex Sigal And Varda Rotter -- Chapter 10. Therapeutic Strategies Based On Pharmacological Modulation Of P53 Pathway / Andrei V. Gudkov. Edited By Gerard P. Zambetti. Includes Bibliographical References And Index. Mode Of Access: World Wide Web. 0387241353......Page 1 Contents......Page 10 1. The p53 Network......Page 12 2. The Three-Dimensional Structure of p53......Page 35 3. Transcriptional Activation by p53: Mechanisms and Targeted Genes......Page 63 4. Transcriptional Repression by the p53 Tumor Suppressor Protein......Page 91 5. Posttranslational Modifications of p53: Upstream Signaling Pathways......Page 105 6. p53 in Human Cancer - Somatic and Inherited Mutations and Mutation-independent Mechanisms......Page 125 7. MDM2 and MDMX Regulators of p53 Activity......Page 165 8. p53 Family Members: p63 and p73......Page 196 9. The Oncogenic Activity of p53 Mutants......Page 208 10. Therapeutic Strategies Based on Pharmacological Modulation of p53 Pathway......Page 233 D......Page 251 M......Page 252 P......Page 253 W......Page 254