p53-Independent Induction of G(1) Arrest and p21(WAF1/CIP1) Expression by Ascofuranone, an Isoprenoid Antibiotic, through Downregulation of c-Myc

Title
p53-Independent Induction of G(1) Arrest and p21(WAF1/CIP1) Expression by Ascofuranone, an Isoprenoid Antibiotic, through Downregulation of c-Myc
Author(s)
장현욱Ji--Hak Jeong[Ji--Hak Jeong]Shin-Sung Kang[Shin-Sung Kang]Kwan-Kyu Park[Kwan-Kyu Park]Junji Magae[Junji Magae]Young Chae Chang[Young Chae Chang]
Keywords
DEPENDENT KINASE MODULATORS; CELL-CYCLE CONTROL; ANTITUMOR ANTIBIOTICS; SIGNALING PATHWAY; TUMOR-SUPPRESSOR; CANCER-CELLS; ASCOCHLORIN; GROWTH; GENE; REPRESSION
Issue Date
201007
Publisher
AMER ASSOC CANCER RESEARCH
Citation
MOLECULAR CANCER THERAPEUTICS, v.9, no.7, pp.2102 - 2113
Abstract
Ascofuranone has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we study the effects of ascofuranone on cell cycle progression in human cancer cells and find that ascofuranone induces G(1) arrest without cytoxicity with upregulation of p53 and p21(WAF1/CIP1) while downregulating c-Myc and G(1) cyclins. Chromatin immunoprecipitation assay and RNA interference studies with cells deficient in p53 and p21 show that ascofuranone induces p21(WAF1/CIP1) expression and subsequent G(1) arrest through the release of p21(WAF1/CIP1) promoter from c-Myc-mediated transcriptional repression, independent of p53. Ascofuranone-induced p21(WAF1/CIP1) associates with CDK2 and prevents CDK2-cyclin E complex formation, leading to the inactivation of E2F transcriptional activity. These results suggest that ascofuranone upregulates p21(WAF1/CIP1) through p53-independent suppression of c-Myc expression, leading to cytostatic G(1) arrest. Thus, ascofuranone represents a unique natural antitumor compound that targets c-Myc independent of p53. Mol Cancer Ther; 9(7); 2102-13. (C) 2010 AACR.
URI
http://hdl.handle.net/YU.REPOSITORY/23933http://dx.doi.org/10.1158/1535-7163.MCT-09-1159
ISSN
1535-7163
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약학대학 > 약학부 > Articles
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