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.

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.

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 past five years have witnessed a remarkable development of interest in cell death 'from inside out'. After 30 years of relative obscurity, its quantitative importance in the building and maintenance of normal tissues, the subtle strategies involved in its regulation, and its significance in the pathogenesis of diseases of major social importance are becoming clear. Moreover, because a distinct set of biological events is involved in this death, these events themselves become reason able targets for new pharmacological agents in the treatment of cancer. The articles in this volume summarize the contents of a discussion meeting held at the Royal Society on 23 and 24 February 1994. The authors are a distinguished international group from a variety of disciplines in biology and medicine and hopefully their articles will convey something of the excitement of this fast-moving field. The three organizers are enormously indebted to all the contributors for the enthusiasm with which they delivered their talks, shared in discussion, and finally committed their contributions to these printed pages. We would also like to acknowledge the gracious way in which the Royal Society hosted the meeting, and in particular Mary Manning for making it the trouble-free and enjoyable experience that it was, and Janet Clifford and Simon Gribbin for skillfully managing the editorial processing of this volume. Michael Dexter June 1994 Martin Raff Andrew Wyllie x 1 Death from inside out: an overVIew ANDREW H.

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.

The third edition is a comprehensive and updated overview of positive and negative effects of UV-exposure, with a focus on Vitamin D and skin cancer. Researchers, oncologists,and students will be provided with the most significant and timely information related to topics such as the epidemiology of skin cancer, the immune system and skin cancer, ultraviolet damage, DNA repair and Vitamin D in Nonmelanoma skin cancer and malignant melanoma. There have been a number of new, scientific findings in this fast moving field that necessitated a thoroughly updated and revised edition including new Vitamin D metabolites and skin cancer, new findings on the beneficial effects of UV and solar UV and skin cancer, adverse effects of sun protection and sunscreens, sun exposure and mortality, and more. The book will summarize essential, up-to-date information for every clinician or scientist interested in how to balance the positive and negative effects of UV‐exposure to minimize the risks of developing vitamin D deficiency and skin cancer.

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.

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.

The last several years have been a landmark period in the ubiquitin field. The breadth of ubiquitin's roles in cell biology was first sketched, and the importance of ubiquitin-dependent proteolysis as a regulatory mechanism gained general acceptance. The many strands of work that led to this new perception are re counted in this book. A consequence of this progress is that the field has grown dramatically since the first book on ubiquitin was published almost a decade ago [M. Rechsteiner (ed. ), Ubiquitin, Plenum Press, 1988]. In this span, students of the cell cycle, transcription, signal transduction, protein sorting, neuropathology, cancer, virology, and immunology have attempted to chart the role of ubi quit in in their particular experimental systems, and this integration of the field into cell biology as a whole continues at a remarkable pace. We hope that for active researchers in the field as well as for newcomers and those on the fence, this book will prove helpful for its breadth, historical perspective, and practical tips. Structural data are now available on many of the components of the ubiquitin pathway. The structures have provided basic insights into the unusual biochemical mechanisms of ubiquitination and proteasome-mediated proteolysis. Because high-speed computer graphics can convey structures more effectively than print media, we have supplemented the figures of the book with a Worldwide Web site that can display the structures in a flexible, viewer-controlled format.