Critical Reviews in Oral Biology & Medicine, Vol 9, 23-37, Copyright © 1998 by International & American Associations for Dental Research
p53--an acrobat in tumorigenesis
U. M. Moll and L. M. Schramm
Department of Pathology, Health Sciences Center, State University of New York at Stony Brook, 11794-8691, USA.
The p53 tumor suppressor protein plays a central role in maintaining
genomic integrity. It does so by occupying a nodal point in the DNA damage
control pathway. When cells are subject to ionizing radiation or other
mutagenic events, p53 mediates cell cycle arrest or programmed cell death
(apoptosis). Furthermore, some evidence suggests that p53 plays a role in
the recognition and repair of damaged DNA. Biochemically, p53 is a
sequence-specific transcriptional stimulator and a non-specific
transcriptional repressor but also engages in multiple protein-protein
interactions. Conversely, disruption of the p53 response pathway strongly
correlates with tumorigenesis. p53 is functionally inactivated by
structural mutations, neutralization by viral products, and non-mutational
cellular mechanisms in the majority of human cancers. p53-deficient mice
have a highly penetrant tumor phenotype, with over 90% tumor incidence
within nine months. In some cancers, direct physical evidence exists
identifying the p53 gene as a target of known environmental carcinogens
such as UV light and benzolalpyrene in cancers of the skin and lung. When
p53 loss occurs, cells do not get repaired or eliminated but rather proceed
to replicate damaged DNA, which results in more random mutations, gene
amplifications, chromosomal re-arrangements, and aneuploidy. In some
experimental models, loss of p53 confers resistance to anticancer therapy
due to loss of apoptotic competence. The translational potential of these
discoveries is beginning to be tested in novel p53-based therapies.
