P53

All of us have lurking in our DNA a most remarkable gene, which has a crucial job - it protects us from cancer. Known simply as p53, this gene constantly scans our cells to ensure that they grow and divide without mishap, as part of the routine maintenance of our bodies. If a cell makes a mistake in copying its DNA during the process of division, p53 stops it in its tracks, summoning a repair team before allowing the cell to carry on dividing. If the mistake is irreparable and the rogue cell threatens to grow out of control, p53 commands the cell to commit suicide. Cancer cannot develop unless p53 itself is damaged or prevented from functioning normally. Perhaps unsurprisingly, p53 is the most studied single gene in history. This book tells the story of medical science's mission to unravel the mysteries of this crucial gene, and to get to the heart of what happens in our cells when they turn cancerous. Through the personal accounts of key researchers, p53: The Gene that Cracked the Cancer Code reveals the fascination of the quest for scientific understanding, as well as the huge excitement of the chase for new cures - the hype, the enthusiasm, the lost opportunities, the blind alleys, and the thrilling breakthroughs. And as the long-anticipated revolution in cancer treatment tailored to each individual patient's symptoms begins to take off at last, p53 remains at the cutting edge. This timely tale of scientific discovery highlights the tremendous recent advances made in our understanding of cancer, a disease that affects more than one in three of us at some point in our lives.

Decades of research on the tumor suppressor p53 have revealed that it plays a significant role as a "guardian of the genome," protecting cells against genotoxic stress. In recent years, p53 research has begun to move into the clinic in attempts to understand how p53 is frequently inactivated in-and sometimes even promotes-human cancer. Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine covers the rapid progress that has recently been made in basic and clinical research on p53. The contributors review new observations about its basic biology, providing updates on the functions of its isoforms and domains, the myriad stresses and signals that trigger its activation or repression, and its downstream effects on genome stability and the cell cycle that enforce tumor suppression in different cell and tissue types. They also discuss how p53 dysfunction contributes to cancer, exploring the various inherited and somatic mutations in the human TP53 gene, the impact of mutant p53 proteins on tumorigenesis, and the prognostic value and clinical outcomes of these mutations. Drugs that are being developed to respond to tumors harboring aberrant p53 are also described. This book is therefore essential reading for all cancer biologists, cell and molecular biologists, and pharmacologists concerned with the treatment of this disease.

This book provides the readers with an overview of research on p53, which has been shown to play a role in numerous crucial biological pathways in normal and cancer cells. Leading scientist in the field, who have all made direct contributions to the understanding of the molecular events underpinning p53 function, have been invited to contribute the various chapters, which discuss the current knowledge of the signaling cascades that are activated by mutations in p53 and overexpression of MDM2, frequently found in human cancer and are major causes of oncogenesis. This book features chapters on the molecular basis of oncogenesis induced by gain of function mutation of p53, signaling pathways induced by MDM2 overexpression, control of mutant or wild-type p53 function by MDM2 and MDMX, p53 mutation in hereditary cancer and structural aspects that activate mutant p53 which can be targeted by drug therapy. This book should be useful for scientists at all levels.

This volume offers a comprehensive review of the functions of the p53 family. The contributors examine the normal roles of these transcription factors, their evolution, the regulatory mechanisms that control p53 activity, and the part played by p53 mutations in tumorigenesis.

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.

p53 has emerged as a key tumor suppressor and important target for novel cancer therapy. This book, written by world-leading p53 researchers including many of those who have shaped the field over the past 25 years, provides unique insights into the progress of the field and the prospects for better cancer diagnosis and therapy in the future.

Since the discovery of p53 as a tumor suppressor, numerous methods have evolved to reveal the unique structural features and biochemical functions of this protein. Several unique properties of p53 posed a challenge to understa- ing its normal function in the initial phase of its research. The low levels of p53 in normal cells, its stabilization under situations of genotoxic stress, induction of growth arrest, and apoptosis with stabilization of the protein, obstructed the visibility of its normal, unmutated function. The property of p53 that can sense a promoter and transactivate or inhibit is still not well understood. It is still not known whether it is the absence of the protein that causes tumorigenesis, or if its mutants have a dominant role in inducing cancer. p53 Protocols comprises eighteen chapters for the study of the diverse properties of p53 and related proteins. The methods included are invaluable for delineating the function of other proteins that may function as tumor suppr- sors or growth suppressors. The chapters are not presented in any schematic order, for the importance and diversity of the functions of p53 make it imp- sible to organize them suitably. We have made a sincere effort to collect the methods most useful to those investigators working on tumor suppressors or growth suppressors. The purpose of p53 Protocols is not only to provide investigators with methods to analyze similar biochemical functions, but also to familiarize them with the associated problems that arose during the course of investigations.

Our understanding of human cancer in the past 40 years has been driven by linking innovative concepts and cutting edge technologies to key problems identified by clinical research. Some of the successes in cancer genetics identified from clinical work have been the identification of specific gene deletions in human chromosomes, the use of PCR-based cloning methodologies to identify and clone human cancer genes, the validation of the human cancer genes using transgenetic technologies in the mouse, and the ability to sequence whole genomes that has recently allowed a collation of all somatic and germline mutations in a human genome. In the same generation, entirely different disciplines involved in basic life science research have used model organisms like yeast, flies, worms, and cancer causing animal viruses as tools to develop windows to see into the machinery of the cell life cycle. The discoveries of pro-apoptotic genes, oncogenes, and covalent control mechanisms like phosphorylation and ubiquitination using the tools of science and technology have all been awarded Nobel prizes for their contribution to our understanding of how cells work. The discovery of p53 using the tumor causing animal virus SV40 falls into this pioneering period of biological and medical research.