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Int. J. Mol. Sci. 2014, 15(10), 17256-17269; doi:10.3390/ijms151017256

Combinatorial Measurement of CDKN1A/p21 and KIF20A Expression for Discrimination of DNA Damage-Induced Clastogenicity

1
Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan
2
Department of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinkuu Ourai Kita, Izumisano, Osaka 598-8531, Japan
*
Author to whom correspondence should be addressed.
Received: 1 July 2014 / Revised: 1 September 2014 / Accepted: 9 September 2014 / Published: 26 September 2014
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Abstract

In vitro mammalian cytogenetic tests detect chromosomal aberrations and are used for testing the genotoxicity of compounds. This study aimed to identify a supportive genomic biomarker could minimize the risk of misjudgments and aid appropriate decision making in genotoxicity testing. Human lymphoblastoid TK6 cells were treated with each of six DNA damage-inducing genotoxins (clastogens) or two genotoxins that do not cause DNA damage. Cells were exposed to each compound for 4 h, and gene expression was comprehensively examined using Affymetrix U133A microarrays. Toxicogenomic analysis revealed characteristic alterations in the expression of genes included in cyclin-dependent kinase inhibitor 1A (CDKN1A/p21)-centered network. The majority of genes included in this network were upregulated on treatment with DNA damage-inducing clastogens. The network, however, also included kinesin family member 20A (KIF20A) downregulated by treatment with all the DNA damage-inducing clastogens. Downregulation of KIF20A expression was successfully confirmed using additional DNA damage-inducing clastogens. Our analysis also demonstrated that nucleic acid constituents falsely downregulated the expression of KIF20A, possibly via p16 activation, independently of the CDKN1A signaling pathway. Our results indicate the potential of KIF20A as a supportive biomarker for clastogenicity judgment and possible mechanisms involved in KIF20A downregulation in DNA damage and non-DNA damage signaling networks. View Full-Text
Keywords: clastogenicity; DNA damage; kinesin family member 20A (KIF20A); cyclin-dependent kinase inhibitor 1A (CDKN1A)/p21; TK6 lymphoblastoid cell line; toxicogenomics clastogenicity; DNA damage; kinesin family member 20A (KIF20A); cyclin-dependent kinase inhibitor 1A (CDKN1A)/p21; TK6 lymphoblastoid cell line; toxicogenomics
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Sakai, R.; Morikawa, Y.; Kondo, C.; Oka, H.; Miyajima, H.; Kubo, K.; Uehara, T. Combinatorial Measurement of CDKN1A/p21 and KIF20A Expression for Discrimination of DNA Damage-Induced Clastogenicity. Int. J. Mol. Sci. 2014, 15, 17256-17269.

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