Peter K. Vogt

Christian Rommel

Bart Vanhaesebroeck

From humble beginnings over 25 years ago as a lipid kinase activity associated with certain oncoproteins, PI3K (phosphoinositide 3-kinase) has been catapulted to the forefront of drug development in cancer, immunity and thrombosis, with the first clinical trials of PI3K pathway inhibitors now in progress. Here we give a brief overview of some key discoveries in the PI3K area and their impact, and include thoughts on the current state of the field, and where it could go from here

Volume 1

Phosphoinositide 3-kinase in Health and Disease

PI3K has become a very intense area of research, with over 2000 publications on PI3K in PubMed for 2009 alone. The expectations for a therapeutic impact of intervention with PI3K activity are high, and progress in the clinical arena is being monitored by many. However, targeted therapies almost invariably encounter roadblocks, often exposing unresolved questions in the basic understanding of the target

Volume 2

Hsing-Jien Kung

Retroviral Insertion and Oncogene Activation

Ronald Swanstrom

This book gives a synthesis of current knowledge on ret- rovirology. Each chapter deals with a different step in the virus life cycle, detailing the molecular aspects of virus replication. The comparison of different retroviruses exemplifies variations. Specific topics include the evolution of retrovirus genomes, integration of the provirus, viral DNA transcriptional and translational control of viral gene expression, processing of viral proteins, and packaging of virion RNA. Data on HIV and HTLV-1 are covered as well as research on animal retrovirus sys- tems.

Strategies of Replication

Retroviruses

An integrated retrovirus effectively becomes part of the cellular genome, but with the difference that the virus to a large extent retains control over its own expression through nontranslated sequences in the long terminal repeat (L TR). Some retroviruses also code for nonstructural proteins that further regulate proviral expression. Integration changes the cell genome; it adds viral genes, and in the case of transducing retroviruses also adds cell-derived oncogenes that have been incorporated into the viral genome. Integration can also have consequences for cellular genes. The transcriptional signals in a provirus can activate expression of neighboring cellular genes; the integration even can disrupt and thus inactivate cellular genes. These effects of retroviral genomes take place in cis; they are referred to as insertional mutagenesis and are the subject of this volume. Almost 10 years have passed since W. Hayward, S. Astrin, and their colleagues found that in B cell lymphomas of chickens, induced by avian leukosis virus, transcription of the cellular proto-oncogene myc was upregulated through the integration of a complete or partial provirus in its vicinity. This landmark discovery suggested a mechanism by which retro viruses that do not carry cellular oncogenes in their genome ("nonacute retroviruses") can cause cancer. It contributed the first evidence for the carcinogen potential of oncogenes that are not part of a viral genome.

Frank J. III Rauscher

Regulation of gene expression at the level of transcription is one of the major determinants of proper cellular proliferation and differentiation. The key players in these processes are sequence-specific DNA binding transcription factor proteins which coordinate programs of gene expression in the nucleus. The articles in this volume document the myriad of genetic and biochemical alterations sustained by human proto-oncogenic transcription factors which result in diverse neoplastic processes. This volume gives insights into how normal programs of gene expression can be subverted by the action of single transcription factors resulting in a specific tumor type. The book provides inspiration for exploiting these tumor-specific alterations as diagnostic, prognostic tools, or as selective therapeutic targets.

Chromosomal Translocations and Oncogenic Transcription Factors

Stephen I. Reed

More than 10 years ago, the discovery of cyclin-dependent ki nases (Cdks) ushered in a new era in the understanding of cell proliferation and its control. Not only were both of the known cell cycle transitions, from G 1 to S phase and G2 to M phase, found to be dependent on these protein kinases, but the reg ulatory assumption intrinsic to cyclin-dependent kinases, a stable inactive catalytic subunit (the Cdk) and an unstable requisite positive regulatory activating subunit (the cyclin), led to a simple model for cell cycle control. Modulation of cyclin accumulation, and thereby Cdk activation, was proposed to be the overarching principle governing the passage through cell cycle phases. An other reality to emerge from the discovery of Cdks was the ex ceptional degree of evolutionary conservation maintained in the machinery and organization of proliferation control. Not only were Cdks shown to be structurally conserved between yeast and man, but mammalian Cdks could substitute functionally for the endogenous enzymes in a yeast cell. The problem of cell cycle control was thought to have been virtually solved. The ensuing years have provided a much more complex view of cell cycle control and the role and regulation of Cdks. The uncritical enthusiasm with which many of the ideas were em braced has required tempering. For example, although Cdks appear to be highly conserved phylogenetically, cyclins are much less so.

Cyclin Dependent Kinase (CDK) Inhibitors

Michael J. Mahan

When it comes to bacterial disease, we are living in a state of false security. Antibiotics have indeed brought unprecedented health benefits, protection from and cure of bacterial diseases during the past 50 years. But there are ominous signs that the fortress and the defenses built on antibiotics are crumbling. They are crum bling because we wittingly or unwittingly created selective con ditions for the emergence of superior pathogens that can no longer be controlled by antibiotics. There are numerous warnings. After a long period of eclipse tuberculosis has now emerged as a serious threat unchecked by antibiotic treatment. Recent years have seen reports of cholera epidemics, of anthrax infections, of serious problems with Salmonella and even with E. coli, just to name a few. Mankind is in a race with microbial invaders. The challenge is to anticipate and respond to developments that affect the precarious balance between man and microbe. This will re quire new knowledge and it will take time for an effective appli cation of that knowledge.

Peter K. Vogt

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