SKP2 Oncogene Is a Direct MYC Target Gene and MYC Down-regulates p27KIP1 through SKP2 in Human Leukemia Cells

Abstract

SKP2 is the ubiquitin ligase subunit that targets p27 KIP1(p27) for degradation. SKP2 is induced in the G 1 -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 up-regulation 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 and activated the SKP2 promoter in luciferase reporter assays. With 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. In a cohort of chronic myeloid leukemia 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. Finally, MYC-induced SKP2 expression resulted in a decrease in p27 protein in K562 cells. Moreover, silencing of SKP2 abrogated the MYC-mediated down-regulation 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.c-MYC (hereafter MYC) is an oncogenic transcription factor of the helix-loop-helix/leucine zipper protein family. MYC exerts a wide array of biological functions in different cellular models related to cell cycle control, genomic instability, energetic metabolism, protein synthesis, intercellular communication, and control of cell differentiation (for reviews see Refs.

The oncoprotein hepatitis B X-interacting protein promotes the migration of ovarian cancer cells through the upregulation of S-phase kinase-associated protein 2 by Sp1

“…Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Overexpression of Skp2 was frequently observed in numerous human cancers, such as ovarian, colorectal, gastric, prostate, lung, sarcoma, breast and other cancers (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). These observations suggest that Skp2 may contribute to the development of human cancers.…”

“…However, the expression and role of HBXIP in ovarian cancer cells is poorly understood. Many studies have shown that overexpression of Skp2 is observed in a variety of human cancers, including ovarian cancer, gastric cancer, colorectal cancer, prostate cancer, sarcoma, breast cancer, lung cancer, pancreatic cancer and other cancers (15,26). In addition, Skp2 has an estab- lished role in the migration of cancer cells.…”

Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma

“…The cell cycle is regulated by various factors, including cyclin, cyclin-dependent kinases (CDKs) and CDK interacting protein (cip)/kinase inhibitory protein (kip). S-phase kinase-associated protein 2 (Skp2) mainly induces the degradation of CDK inhibitors, including p21 cip1 , p27 kip1 and p57 kip2 (19)(20)(21). As an F-box protein, Skp2 is a key regulator for cell cycle progression.…”

The Proteasome as a Therapeutic Target in Chronic Myeloid Leukemia

“…Moreover, exogenous p27 kip1 expression partially antagonizes the effect of Bcr-Abl on proliferation (Albero et al, 2010;Andreu et al, 2005;Bretones et al, 2011;Jonuleit et al, 2000). By inhibiting the tyrosine kinase activity of BcrAbl with Imatinib, the half-life of p27 kip1 is increased, meaning that Bcr-Abl induces the degradation of p27 kip1 .…”

“…Ignacio Peŕez-Roger and Mariá Pilar Albero (2011). The Proteasome as a Therapeutic Target in Chronic Myeloid Leukemia, Myeloid Leukemia -Basic Mechanisms of Leukemogenesis, Dr Steffen Koschmieder (Ed.…”