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Brief Report
CD28 Costimulation Mediates Transcription of SKP2 and CKS1, the Substrate Recognition Components of SCFSkp2 Ubiquitin Ligase That Leads p27kip1 to Degradation
Leonard J. Appleman, Irina Chernova, Lequn Li and Vassiliki A. Boussiotis
volume 5 | issue 18
15 september 2006Pages: 2123 - 2129
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Activation through TCR/CD3-plus-CD28 induces primary T lymphocytes to enter S phase. Downregulation of cyclin-dependent kinase inhibitor p27kip1 is critical in this process and is mediated by ubiquitin-targeted degradation of p27kip1. Ubiquitination of p27kip1 is performed by the SCFskp2 ubiquitin ligase comprised of the core components Roc1, Cul1 and Skp1 and the substrate recognition components Skp2 and Cks1. Here we show that in primary human T lymphocytes, the SCFskp2 core components Roc1, Cul1 and Skp1 are constitutively expressed and their levels remain unchanged upon TCR/CD3-plus-CD28 costimulation. In contrast, the substrate recognition components Skp2 and Cks1 are almost undetectable and are transcriptionally induced upon costimulation. We determined that the SKP2 promoter lies directly upstream of the transcription start site and contains binding sites for SP1, Elk-1 and E2F transcription factors. Mutagenesis of SP1 and Elk-1 sites abrogated TCR/CD3-plus-CD28-mediated SKP2 promoter-driven reporter activity, whereas mutagenesis of E2F site enhanced reporter activity, suggesting that SKP2 promoter may act as a node of integration for mitogenic and anti-mitogenic signals. Thus, in primary T lymphocytes CD28 costimulation can directly regulate cell cycle progression by inducing transcription of the substrate recognition components of SCFskp2 ubiquitin ligase that targets p27kip1 for degradation.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.