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Polo-like kinase 1 enhances survival and mutagenesis after genotoxic stress in normal cells through cell cycle checkpoint bypass.

Publication ,  Journal Article
Chun, G; Bae, D; Nickens, K; O'Brien, TJ; Patierno, SR; Ceryak, S
Published in: Carcinogenesis
May 2010

Polo-like kinase 1 (Plk1) is a key regulator of mitosis. Aberrant Plk1 activity is found in tumors, but little is known regarding its role in the DNA damage response of normal cells and its potential contribution to the early stages of carcinogenesis. Inappropriate survival signaling after DNA damage may facilitate clonal expansion of genetically compromised cells, and it is known that protein tyrosine phosphatase (PTP) inhibitors activate key survival pathways. In this study, we employed hexavalent chromium [Cr(VI)], a well-documented genotoxicant, to investigate the mechanism by which survival pathway activation could lead to loss of checkpoint control via a mechanism involving Plk1. We recently reported that PTP inhibition enhances clonogenic survival and mutagenesis after Cr(VI) exposure by overriding Cr-induced growth arrest. Here, we report that checkpoint bypass, facilitated by PTP inhibition, was associated with decreased Cdk1 Tyr15 phosphorylation, as well as increased Plk1 activity and nuclear localization. Plk1 was necessary for increased survival after PTP inhibition and Cr(VI) exposure in normal human fibroblasts via enhanced mitotic progression. In addition, pharmacological inhibition of Plk1 abolished the PTP inhibitor-induced bypass of the G(2)/M checkpoint. Notably, Plk1 overexpression increased survival and mutagenesis after Cr(VI) exposure in wild-type Saccharomyces cerevisiae. Taken together, our data indicate that Plk1 activation and nuclear localization are necessary for PTP-regulated mitotic progression after DNA damage. Our studies highlight a role for Plk1 in the loss of checkpoint control, increased survival and mutagenesis after genotoxic exposure in normal cells, which in turn may lead to genomic instability and carcinogenesis.

Duke Scholars

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

May 2010

Volume

31

Issue

5

Start / End Page

785 / 793

Location

England

Related Subject Headings

  • Saccharomyces cerevisiae
  • Proto-Oncogene Proteins
  • Protein Tyrosine Phosphatases
  • Protein Serine-Threonine Kinases
  • Polo-Like Kinase 1
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mutagenesis
  • Mitosis
  • Humans
 

Citation

APA
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MLA
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Chun, G., Bae, D., Nickens, K., O’Brien, T. J., Patierno, S. R., & Ceryak, S. (2010). Polo-like kinase 1 enhances survival and mutagenesis after genotoxic stress in normal cells through cell cycle checkpoint bypass. Carcinogenesis, 31(5), 785–793. https://doi.org/10.1093/carcin/bgq014
Chun, Gina, Dongsoon Bae, Kristen Nickens, Travis J. O’Brien, Steven R. Patierno, and Susan Ceryak. “Polo-like kinase 1 enhances survival and mutagenesis after genotoxic stress in normal cells through cell cycle checkpoint bypass.Carcinogenesis 31, no. 5 (May 2010): 785–93. https://doi.org/10.1093/carcin/bgq014.
Chun G, Bae D, Nickens K, O’Brien TJ, Patierno SR, Ceryak S. Polo-like kinase 1 enhances survival and mutagenesis after genotoxic stress in normal cells through cell cycle checkpoint bypass. Carcinogenesis. 2010 May;31(5):785–93.
Chun, Gina, et al. “Polo-like kinase 1 enhances survival and mutagenesis after genotoxic stress in normal cells through cell cycle checkpoint bypass.Carcinogenesis, vol. 31, no. 5, May 2010, pp. 785–93. Pubmed, doi:10.1093/carcin/bgq014.
Chun G, Bae D, Nickens K, O’Brien TJ, Patierno SR, Ceryak S. Polo-like kinase 1 enhances survival and mutagenesis after genotoxic stress in normal cells through cell cycle checkpoint bypass. Carcinogenesis. 2010 May;31(5):785–793.
Journal cover image

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

May 2010

Volume

31

Issue

5

Start / End Page

785 / 793

Location

England

Related Subject Headings

  • Saccharomyces cerevisiae
  • Proto-Oncogene Proteins
  • Protein Tyrosine Phosphatases
  • Protein Serine-Threonine Kinases
  • Polo-Like Kinase 1
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mutagenesis
  • Mitosis
  • Humans