Cul7/p185/p193 Binding to Simian Virus 40 Large T Antigen Has a Role in Cellular Transformation

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Abstract
Simian virus 40 large T antigen (TAg) is a viral oncoprotein that can promote cellular transformation. TAg9s 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.