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SKP2 oncogene is a MYC target gene in human leukemia cells

AuthorsLeón, Javier ; Bretones, Gabriel ; Acosta, Juan C.; Caraballo, Juan M. ; Ferrándiz, Nuria
Issue Date2010
CitationEACR 21 (2010)
Abstract[Background]: SKP2 gene is frequently overexpressed in human cancers and has been associated with tumour progression. SKP2 is the ubiquitin ligase subunit that targets p27KIP1 for degradation, and the levels of SKP2 and p27 inversely correlale in many tumours and cell models. MYC antagonizes p27 inhibitory activity in cell cycle. [Material and Methods]: We used human leukemia K562 cells carrying zinc-inducible MYC transgenes and tamoxifen-activable MycER proteins. The expression of SKP2 was assayed at the mRNA level by qRT-PCR and at the protein level by immunoblot. The binding of MYC to SKP2 promoter was analysed by chromatin and the transcriptional activity of MYC was assessed by rerpoter luciferase assays. [Results]: MYC induces SKP2 expression at the mRNA and protein levels in four different models based in K562 cells with conditional MYC expression. SKP2 up-regulation was independent from cell cycle. MYC up-regulates SKP2 mRNA expression when protein synthesis is inhibited, binds to a 5' region of human SKP2 that includes an E-box. Silencing of MYC by siRNA results in SKP2 down-regulation. MYC also regulated SKP2 in a human Iymphoid and mink epithelial cell lines with conditional MYC expression. We also found that the MYC-induced expression of SKP2 resulted in decreased in p27 protein in K562 cells. siRNA-mediated silencing of SKP2 resultked in increased p27 but had no effect on MYC levels or activity. Moreover, MYC induced the phosphorylation of p27 in Thr-187 and the association of p27 with CDK-cyclin complexes, a prerequisite for p27 being targeted by SKP2. [Conclusions]: Altogether, our data shows that SKP2 is a direct target gene of MYC at least in human leukemia K562 cells, and that SKP2 regulation Ieads to reduced p27 levels in this model. The results suggest a new mechanism for the MYC transformation activity through the up-regulalion of the SKP2 oncogene and the reduction of p27 levels in tumour cells.
DescriptionTrabajo presentado al "21th Meeting of the European Association for Cancer Research" celebrado en Oslo (Noruega) del 26 al 29 de junio de 2010.-- et al.
Appears in Collections:(IBBTEC) Comunicaciones congresos
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