Cul7/p185/p193 binding to simian virus 40 large T antigen has a role in cellular transformation.
Simian virus 40 large T antigen (TAg) is a viral oncoprotein that can promote cellular transformation. TAg's transforming activity results in part by binding and inactivating key tumor suppressors, including p53 and the retinoblastoma protein (pRb). We have identified a TAg-associated 185-kDa protein that has significant homology to the cullin family of E3 ubiquitin ligases. TAg binds to an SCF-like complex that contains p185/Cul7, Rbx1, and the F box protein Fbw6. This SCF-like complex binds to an N-terminal region of TAg. Several p185/Cul7-binding-deficient mutants of TAg were generated that retained binding to pRb and p53 and were capable of overcoming Rb-mediated repression of E2F transcription. Despite binding to pRb and p53, these p185/Cul7-binding-defective mutants of TAg were unable to transform primary mouse embryo fibroblasts. Cells expressing p185/Cul7-binding-defective mutants of TAg were unable to grow to high density or grow in an anchorage-independent manner as determined by growth in soft agar. Considering the significance of other TAg-interacting proteins in regulation of the cell cycle, p185/Cul7 may also regulate an important growth control pathway.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Syed Hamid
SH
Ali
Jocelyn S
JS
Kasper
Takehiro
T
Arai
James A
JA
DeCaprio
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism*; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D013539:Simian virus 40 / Q000502:physiology*
D000957:Antigens, Viral, Tumor; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; C494817:Cul7 protein, mouse; D044842:Cullin Proteins