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Differential Cellular Effects of Plk1 Inhibitors Targeting the ATP-binding Domain or Polo-box Domain

Title
Differential Cellular Effects of Plk1 Inhibitors Targeting the ATP-binding Domain or Polo-box Domain
Author
임형신
Keywords
DNA-DAMAGE CHECKPOINT; CANCER-CELLS; CYCLE ARREST; KINASE 1; THYMOQUINONE; POLO-LIKE-KINASE-1; DEPLETION; PROGRESSION; REGULATOR; DISCOVERY
Issue Date
2015-12
Publisher
WILEY-BLACKWELL
Citation
JOURNAL OF CELLULAR PHYSIOLOGY, v. 230, No. 12, Page. 3057-3067
Abstract
The expression of polo-like kinase 1 (Plk1) correlates with malignancy and is thus recognized as a target for cancer therapy. In addition to the development of ATP-competitive Plk1 inhibitors, the polo-box domain (PBD), a unique functional domain of PLKs, is being targeted to develop Plk1-specific inhibitors. However, the action mechanisms of these two classes of Plk1 inhibitors have not been thoroughly evaluated. Here, we evaluate the differences in cellular effects of ATP-binding domain inhibitors (BI 2536, GSK 461364) and PBD inhibitors (poloxin, thymoquinone) to determine their mechanisms of Plk1 inhibition. Our data show that BI 2536 and GSK461364 increased the population of cells in the G2/M phase compared with controls, while treatment with poloxin and thymoquinone increased cell population in the S phase as well as in G2/M, in a p53-independent manner. The population of cells staining positively for p-Histone H3 and MPM2, mitotic index, was increased by treatment with BI 2536 or GSK461364, but not by treatment with poloxin or thymoquinone. Furthermore, treatment with BI 2536 or GSK461364 resulted in activation of the BubR1 spindle checkpoint kinase, suggesting that treatment with ATP-binding domain inhibitors induces metaphase arrest. However, the administration of poloxin and thymoquinone resulted in an increase in p21(WAF1) and S arrest, indicating that PBD inhibitors also affected interphase before mitotic entry. Taken together, these data suggest that the PDB of Plk1 plays a role in S phase progression through interaction with other proteins, while its ATP-binding domain is important for regulating mitotic progression mediated by its catalytic activity involving consumption of ATP. (C) 2015 Wiley Periodicals, Inc.
URI
http://onlinelibrary.wiley.com/doi/10.1002/jcp.25042/fullhttp://repository.hanyang.ac.kr/handle/20.500.11754/102044
ISSN
0021-9541; 1097-4652
DOI
10.1002/jcp.25042
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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