Title |
Targeting the Oncogenic E3 Ligase Skp2 in Prostate and Breast Cancer Cells with a Novel Energy Restriction-Mimetic Agent
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Published in |
PLOS ONE, October 2012
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DOI | 10.1371/journal.pone.0047298 |
Pubmed ID | |
Authors |
Shuo Wei, Po-Chen Chu, Hsiao-Ching Chuang, Wen-Chun Hung, Samuel K. Kulp, Ching-Shih Chen |
Abstract |
Substantial evidence supports the oncogenic role of the E3 ubiquitin ligase S-phase kinase-associated protein 2 (Skp2) in many types of cancers through its ability to target a broad range of signaling effectors for ubiquitination. Thus, this oncogenic E3 ligase represents an important target for cancer drug discovery. In this study, we report a novel mechanism by which CG-12, a novel energy restriction-mimetic agent (ERMA), down-regulates the expression of Skp2 in prostate cancer cells. Pursuant to our previous finding that upregulation of β-transducin repeat-containing protein (β-TrCP) expression represents a cellular response in cancer cells to ERMAs, including CG-12 and 2-deoxyglucose, we demonstrated that this β-TrCP accumulation resulted from decreased Skp2 expression. Evidence indicates that Skp2 targets β-TrCP for degradation via the cyclin-dependent kinase 2-facilitated recognition of the proline-directed phosphorylation motif (412)SP. This Skp2 downregulation was attributable to Sirt1-dependent suppression of COP9 signalosome (Csn)5 expression in response to CG-12, leading to increased cullin 1 neddylation in the Skp1-cullin1-F-box protein complex and consequent Skp2 destabilization. Moreover, we determined that Skp2 and β-TrCP are mutually regulated, providing a feedback mechanism that amplifies the suppressive effect of ERMAs on Skp2. Specifically, cellular accumulation of β-TrCP reduced the expression of Sp1, a β-TrCP substrate, which, in turn, reduced Skp2 gene expression. This Skp2-β-TrCP-Sp1 feedback loop represents a novel crosstalk mechanism between these two important F-box proteins in cancer cells with aberrant Skp2 expression under energy restriction, which provides a proof-of-concept that the oncogenic Csn5/Skp2 signaling axis represents a "druggable" target for this novel ERMA. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
India | 1 | 4% |
Unknown | 27 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 14 | 50% |
Researcher | 6 | 21% |
Student > Bachelor | 3 | 11% |
Professor | 1 | 4% |
Lecturer | 1 | 4% |
Other | 2 | 7% |
Unknown | 1 | 4% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 11 | 39% |
Biochemistry, Genetics and Molecular Biology | 8 | 29% |
Medicine and Dentistry | 2 | 7% |
Business, Management and Accounting | 1 | 4% |
Chemistry | 1 | 4% |
Other | 0 | 0% |
Unknown | 5 | 18% |