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Suppression of c-Myc enhances p21(WAF1/CIP1)-mediated G1 cell cycle arrest through the modulation of ERK phosphorylation by ascochlorin

Authors
Jeong, Yun-JeongHoe, Hyang-SookCho, Hyun-JiPark, Kwan-KyuKim, Dae-DongKim, Cheorl-HoMagae, JunjiKang, Dong WookLee, Sang-RaeChang, Young-Chae
Issue Date
Feb-2018
Publisher
WILEY
Keywords
ascochlorin; c-Myc; ERK; G1 cell cycle arrest
Citation
JOURNAL OF CELLULAR BIOCHEMISTRY, v.119, no.2, pp.2036 - 2047
Journal Title
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume
119
Number
2
Start Page
2036
End Page
2047
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/753
DOI
10.1002/jcb.26366
ISSN
0730-2312
Abstract
Numerous anti-cancer agents inhibit cell cycle progression via a p53-dependent mechanism; however, other genes such as the proto-oncogene c-Myc are promising targets for anticancer therapy. In the present study, we provide evidence that ascochlorin, an isoprenoid antibiotic, is a non-toxic anti-cancer agent that induces G1 cell cycle arrest and p21(WAF1/CIP1) expression by downregulating of c-Myc protein expression. Ascochlorin promoted the G1 arrest, upregulated p53 and p21(WAF1/CIP1), and downregulated c-Myc in HCT116 cells. In p53-deficient cells, ascochlorin enhanced the expression of G1 arrest-related genes except p53. Small interfering RNA (siRNA) mediated c-Myc silencing indicated that the transcriptional repression of c-Myc was related to ascochlorin-mediated modulation of p21(WAF1/CIP1) expression. Ascochlorin suppressed the stabilization of the c-Myc protein by inhibiting ERK and P70S6K/4EBP1 phosphorylation, whereas it had no effect on c-Myc degradation mediated by PI3K/Akt/GSK3. The ERK inhibitor PD98059 and siRNA-mediated ERK silencing induced G1 arrest and p21(WAF1/CIP1) expression by downregulating c-Myc in p53-deficient cells. These results indicated that ascochlorin-induced G1 arrest is associated with the repression of ERK phosphorylation and c-Myc expression. Thus, we reveal a role for ascochlorin in inhibiting tumor growth via G1 arrest, and identify a novel regulatory mechanism for ERK/c-Myc.
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연구본부 (퇴행성뇌질환 연구그룹)
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