Nature 380, 262 - 265 (21 March 1996); doi:10.1038/380262a0

Inactivation of p27^Kip1 by the viral E1A oncoprotein in TGF-treated cells

Asoke Mal, Randy Y. C. Poon^*, Philip H. Howe^†, Hideo Toyoshima^*, Tony Hunter^* & Marian L. Harter^‡

Departments of Molecular Biology and ^‡Cell Biology, Cleveland Clinic Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
^*The Salk Institute, La Jolla, California 92037, USA
^‡To whom correspondence should be addressed.

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)- on mink lung epithelial cells^1,2: exposure of TGF- 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 p15^Ink4B (ref. 4), inactiva-tion of the cyclin E/A-cdk2 complex by the inhibitory protein p27^Kip1 (refs 5–7), and with the accumulation of unphos-phorylated retinoblastoma protein⁸. The rescue by E1A of cells from TGF- arrest is partly independent of its binding to retinoblastoma protein¹. Here we show that E1A directly affects the c\din-dependent kinase inhibitor p27^Kip1 in TGF--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- 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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