Enterocyte proliferation and intestinal hyperplasia induced by simian virus 40 T antigen require a functional J domain.
Transgenic mice expressing the simian virus 40 large T antigen (TAg) in enterocytes develop intestinal hyperplasia that progresses to dysplasia with age. This induction requires TAg action on the retinoblastoma (Rb) family of tumor suppressors and is independent of the p53 pathway. In cell culture systems, the inactivation of Rb proteins requires both a J domain in TAg that interacts with hsc70 and an LXCXE motif that directs association with Rb proteins. Together these elements are sufficient to release E2Fs from their association with Rb family members. We have generated transgenic mice that express a J domain mutant (D44N) in villus enterocytes. In contrast to wild-type TAg, the D44N mutant is unable to induce enterocyte proliferation. Histological and morphological examination revealed that mice expressing the J domain mutant have normal intestines without loss of growth control. Unlike mice expressing wild-type TAg, mice expressing D44N do not reduce the protein levels of p130 and are also unable to dissociate p130-E2F DNA binding complexes. Furthermore, mice expressing D44N in a null p130 background are still unable to develop hyperplasia. These studies demonstrate that the ectopic proliferation of enterocytes by TAg requires a functional J domain and suggest that the J domain is necessary to inactivate all three pRb family members.
Rathi
Abhilasha V
AV
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Sáenz Robles
M Teresa
MT
Pipas
James M
JM
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D020895:Enterocytes / Q000166:cytology / Q000821:virology*; D006965:Hyperplasia / Q000821:virology*; D007150:Immunohistochemistry; D007422:Intestines / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D027601:Polyomavirus Infections / Q000473:pathology; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics / Q000502:physiology*; D014412:Tumor Virus Infections / Q000473:pathology
D000952:Antigens, Polyomavirus Transforming; D016160:Retinoblastoma Protein