[Frontiers in Bioscience 15, 1172-1190, June 1, 2010]

p53 as the main traffic controller of the cell signaling network

Sinto Sebastian1, Amalia Azzariti1, Nicola Silvestris2, Letizia Porcelli1, Antonio Russo3 Massimo Tommasino4 and Angelo Paradiso1

1Clinical Experimental Oncology Laboratory, National Cancer Institute "Giovanni Paolo II", Via Hahnemann, 10 - 70126 Bari, Italy,2Medical and Experimental Oncology Unit, National Cancer Institute "Giovanni Paolo II", Via Hahnemann, 10 - 70126 Bari, Italy,3 Section of Medical Oncology, Department of Surgery and Oncology, University of Palermo, Palermo, Italy,4Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Unexpected roles of p53 as a major traffic controller
4. p53 as traffic controller: modes of activation and signaling mechanism
4.1. DNA damage
4.2. Oncogene activation
4.3. Hypoxia
4.4. Microtubule disruption
4.5. Replicative senescence
5. The elegant model of p53 regulation
6. p53 ability to switch on and off genes
7. Events downstream of the p53 activation
7.1. Growth arrest
7.2. DNA repair
7.3. Apoptosis
7.3.1. p53 role in transcription dependent apoptosis
7.3.2. Role of p53 in transcription independent apoptosis
8. Dysfunction of p53 traffic controller in human cancer
8.1. Polymorphisms in TP53
8.2. Mutations in TP53
8.3. Virus infections
8.4. p53 family isoforms
9. Concluding notes
10. References

1. ABSTRACT

Among different pathological conditions that affect human beings, cancer has received a great deal of attention primarily because it leads to significant morbidity and mortality. This is essetnially due to increasing world-wide incidence of this disease and the inability to discover the cause and molecular mechanisms by which normal human cells acquire the characteristics that define cancer cells. Since the discovery of p53 over a quarter of a century ago, it is now recognized that virtually all cell fate pathways of live cells and the decision to die are under the control of p53. Such extensive involvement indicates that p53 protein is acting as a major traffic controller in the cell signaling network. In cancer cells, many cell signaling pathways of normal human cells are rerouted towards immortalization and this is accomplished by the corruption of the main controllers of cell signaling pathways such as p53. This review highlights how p53 signaling activity is altered in cancer cells so that cells acquire the hallmarks of cancer including deregulated infinite self replicative potential.