Tissue-specific inactivation of p53 tumor suppression in the mouse.
The p53 gene is the most frequent target of structural and functional genetic mutations in human cancer. Thus, considerable effort has been devoted to mapping the functional domains of p53 with regard to their impact on tumorigenesis in vivo. Studies have shown that the carboxy-terminal domain of p53 is sufficient for transformation in vitro. To determine whether a transdominant-negative p53 protein could be used to elicit a tissue-specific p53-null effect in vivo, we tested whether a carboxy-terminal p53 fragment (amino acids 302-390) could abolish p53-dependent apoptosis in an established tumor progression model. We showed previously that loss of p53-dependent apoptosis accelerates brain tumorigenesis in a transgenic mouse model. Here, we show that the same effect can be elicited by expressing a dominant-negative p53 protein tissue specifically in the presence of wild-type p53. Transgenic mice in which pRb function has been disrupted and that coexpress a p53 carboxy-terminal dominant-negative fragment (p53DD) develop aggressive brain tumors mimicking genetic loss of p53 in this model. Inactivation of endogenous p53, which we show to be complexed with p53DD, results in a reduction in apoptosis and acceleration of tumorigenesis. These studies establish a mechanism for tissue-specific knock out of p53 function in vivo.
Bowman
T
T
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27299, USA.
Symonds
H
H
Gu
L
L
Yin
C
C
Oren
M
M
Van Dyke
T
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D016545:Choroid Plexus Neoplasms / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D013489:Suppression, Genetic; D016019:Survival Analysis; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53