Abstract
THE adenovirus oncoprotein E1A and the simian virus SV40 large T antigen can both reverse the strong growth-inhibitory effect of transforming growth factor(TGF)-β on mink lung epithelial cells1,2: exposure of TGF-β causes these cells to arrest late in the Gl phase of the cell cycle (ref. 3). This arrest correlates with an increase in expression of the protein p15Ink4B (ref. 4), inactiva-tion of the cyclin E/A-cdk2 complex by the inhibitory protein p27Kip1 (refs 5–7), and with the accumulation of unphos-phorylated retinoblastoma protein8. The rescue by E1A of cells from TGF-β arrest is partly independent of its binding to retinoblastoma protein1. Here we show that E1A directly affects the c\din-dependent kinase inhibitor p27Kip1 in TGF-β-treated cells by binding to it and blocking its inhibitory effect, thereby restoring the activity of the cyclin–cdk2 kinase complex. In this way, E1A can overcome the effect of TGF-β and modulate the cell cycle. To our knowledge, E1A provides the first example of a viral oncoprotein that can disable a cellular protein whose function is to inhibit the activity of cyclin-dependent kinases.
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Mal, A., Poon, R., Howe, P. et al. Inactivation of p27Kip1 by the viral E1A oncoprotein in TGFβ-treated cells. Nature 380, 262–265 (1996). https://doi.org/10.1038/380262a0
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DOI: https://doi.org/10.1038/380262a0
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