Eμ–Myc transgenic mice overexpress Myc and develop B-cell lymphomas that resemble human Burkitt lymphoma. The E2F1 transcription factor, a MYC target gene, is thought to be necessary, but not sufficient, for the MYC-mediated downregulation of p27 expression in these mice. Therefore, Cleveland and colleagues wanted to identify proteins other than E2F1 that might function downstream of MYC to mediate p27 downregulation. The expression of p27 is regulated at the transcriptional and protein levels, and MYC-dependent downregulation of p27 appears to be primarily achieved by modulating p27 protein stability. p27 is targeted for proteolysis by S-phase kinase-associated protein 2 (SKP2) and cyclin-dependent kinase subunit 1 (CKS1), both of which form the p27 phosphodegron binding site of the SCFSKP2 ubiquitin ligase holoenzyme. Indeed, using expression profiling of lymphomas from Eμ–Myc mice, the authors showed that Cks1 and to a lesser extent Skp2 were overexpressed in precancerous B cells from Eμ–Myc mice. Although they showed that the induction of transcription of Cks1 was MYC-dependent, this was indirect and could not be attributed to E2F1, nor to forkhead box M1 (FOXM1), a transcription factor that regulates the expression of Cks1 and Skp2.
So, is MYC-mediated transcription of Cks1 responsible for the tumorigenic downregulation of p27? Using quantitative reverse transcription PCR and western blotting to analyse 49 lymphomas from Eμ–Myc mice and 17 human Burkitt lymphoma samples, Cleveland and colleagues showed that p27 was commonly downregulated whereas CKS1 and SKP2 were overexpressed, suggesting that this expression profile could represent a hallmark of MYC-induced lymphoma. In addition, they showed that Eμ–Myc;Cks1−/− mice had a marked delay in lymphoma development and prolonged survival. Next, they confirmed that this MYC–CKS1 pathway increased B-cell proliferation rates in vivo owing to p27 downregulation, and that CKS1 was required for MYC to downregulate p27. Importantly, they also showed that lymphomas from Eμ–Myc;Cks1−/− mice continued to express p27 and were less invasive, demonstrating the relevance of the MYC–CKS1 pathway in lymphomagenesis.
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