Simian virus 40 large T antigen's association with the CUL7 SCF complex contributes to cellular transformation.
Simian virus 40 large T antigen (T Ag) is capable of immortalizing and transforming rodent cells. The transforming activity of T Ag is due in large part to perturbation of the tumor suppressor proteins p53 and the retinoblastoma (pRB) family members. Inactivation of these tumor suppressors may not be sufficient for T Ag-mediated cellular transformation. It has been shown that T Ag associates with an SCF-like complex that contains a member of the cullin family of E3 ubiquitin ligases, CUL7, as well as SKP1, RBX1, and an F-box protein, FBXW8. We identified T Ag residues 69 to 83 as required for T Ag binding to the CUL7 complex. We demonstrate that delta69-83 T Ag, while it lost its ability to associate with CUL7, retained binding to p53 and pRB family members. In the presence of CUL7, wild-type (WT) T Ag but not delta69-83 T Ag was able to induce proliferation of mouse embryo fibroblasts, an indication of cellular transformation. In contrast, WT and delta69-83 T Ag enabled mouse embryo fibroblasts to proliferate to similarly high densities in the absence of CUL7. Our data suggest that, in addition to p53 and the pRB family members, T Ag serves to bind to and inactivate the growth-suppressing properties of CUL7. In addition, these results imply that, at least in the presence of T Ag, CUL7 may function as a tumor suppressor.
Kasper
Jocelyn S
JS
Dana-Farber Cancer Institute, Department of Medical Oncology and Harvard Medical School, Mayer Building 457, 44 Binney Street, Boston, MA 02115, USA.
Kuwabara
Hiroshi
H
Arai
Takehiro
T
Ali
Syed Hamid
SH
DeCaprio
James A
JA
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D002455:Cell Division; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013539:Simian virus 40 / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D046912:Multiprotein Complexes; D016159:Tumor Suppressor Protein p53; D044843:SKP Cullin F-Box Protein Ligases