Intestinal dysplasia induced by simian virus 40 T antigen is independent of p53.
Transgenic mice expressing simian virus 40 large T antigen in enterocytes develop intestinal hyperplasia that progresses to dysplasia with age. Hyperplasia is dependent on T antigen binding to the retinoblastoma (pRb) family of tumor suppressor proteins. Mice expressing a truncated T antigen that inactivates the pRb-family, but is defective for binding p53, exhibit hyperplasia but do not progress to dysplasia. We hypothesized that the inhibition of the pRb family leads to entry of enterocytes into the cell cycle, resulting in hyperplasia, while inactivation of p53 is required for progression to dysplasia. Therefore, we examined T antigen/p53 complexes from the intestines of transgenic mice. We found that T antigen did not induce p53 stabilization, and we could not detect T antigen/p53 complexes in villus enterocytes. In contrast, T antigen expression led to a large increase in the levels of the cyclin-dependent kinase inhibitor p21. Furthermore, mice in which pRb was inactivated by a truncated T antigen in a p53 null background exhibited intestinal hyperplasia but no progression to dysplasia. These data indicate that loss of p53 function does not play a role in T antigen-induced dysplasia in the intestine. Rather, some unknown function of T antigen is essential for progression beyond hyperplasia.
Markovics
Jennifer A
JA
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Carroll
Patrick A
PA
Robles
M Teresa Sáenz
MT
Pope
Hannah
H
Coopersmith
Craig M
CM
Pipas
James M
JM
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D016158:Genes, p53; D006965:Hyperplasia / Q000473:pathology; D007414:Intestinal Neoplasms / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D013539:Simian virus 40 / Q000472:pathogenicity*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000952:Antigens, Polyomavirus Transforming; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53