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SKP2 oncogene is a direct MYC target gene and MYC downregulates p27KIP1 through SKP2 in human leukemia cells

AuthorsBretones, Gabriel ; Acosta, Juan C.; Caraballo, Juan M. ; Ferrándiz, Nuria ; Gómez-Casares, M. Teresa; Albajar, Marta ; Blanco, Rosa ; Ruiz, Paula; León, Javier
Cell cycle
Ubiquitin ligase
Issue DateJan-2011
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 286(11): 9815 (2011)
AbstractSKP2 is the ubiquitin ligase subunit that targets p27KIP1 (p27) for degradation. SKP2 is induced in the G1-S transit of the cell cycle, is frequently overexpressed in human cancer, and displays transformation activity in experimental models. Here we show that MYC induces SKP2 expression at the mRNA and protein levels in human myeloid leukemia K562 cells with conditional MYC expression. Importantly, in these systems, induction of MYC did not activate cell proliferation, ruling out SKP2 upregulation as a consequence of cell cycle entry. MYC-dependent SKP2 expression was also detected in other cell types such as lymphoid, fibroblastic and epithelial cell lines. MYC-induced SKP2 mRNA expression in the absence of protein synthesis activated the SKP2 promoter in luciferase reporter assays. By chromatin immunoprecipitation assays MYC was detected bound to a region of human SKP2 gene promoter that includes E-boxes. The K562 cell line derives from human chronic myeloid leukemia (CML). In a cohort of CML bone marrow samples we found a correlation between MYC and SKP2 mRNA levels. Analysis of cancer expression databases also indicated a correlation between MYC and SKP2 expression in lymphoma. MYC-induced SKP2 expression resulted in a decrease in p27 protein in K562 cells. Moreover, silencing of SKP2 abrogated the MYC-mediated downregulation of p27. Our data show that SKP2 is a direct MYC target gene and that MYC-mediated SKP2 induction leads to reduced p27 levels. The results suggest the induction of SKP2 oncogene as a new mechanism for MYC-dependent transformation.
Description23 páginas, 9 figuras.-- et al.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M110.165977
Appears in Collections:(IBBTEC) Artículos
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