p53-dependent apoptosis suppresses tumor growth and progression in vivo.
To determine the contribution of p53 loss to tumor progression, we have induced abnormal proliferation in the brain choroid plexus epithelium of transgenic mice using a SV40 T antigen fragment that perturbs pRB family function but does not affect p53 function. Tumors induced by this mutant develop slowly compared with those induced by wild-type T antigen. Suppressed tumor growth is directly attributable to p53 function, since rapid tumor development occurs when the T antigen fragment is expressed in p53-null mice. In p53-heterozygous mice, stochastic loss of the wild-type p53 allele results in the focal emergence of aggressive tumor nodules characteristic of tumor progression. In each case, aggressive tumor development in the absence of p53 function corresponds to a decrease in the level of apoptosis. These results provide in vivo evidence that p53-dependent apoptosis, occurring in response to oncogenic events, is a critical regulator of tumorigenesis.
Symonds
H
H
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill 27599.
Krall
L
L
Remington
L
L
Saenz-Robles
M
M
Lowe
S
S
Jacks
T
T
Van Dyke
T
T
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D002831:Choroid Plexus / Q000502:physiology; D016545:Choroid Plexus Neoplasms / Q000235:genetics / Q000473:pathology*; D003433:Crosses, Genetic; D004848:Epithelium; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000952:Antigens, Polyomavirus Transforming; D016159:Tumor Suppressor Protein p53