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

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.

Systematic identification of an integrative network module during senescence from time-series gene expression

“…As has been demonstrated by several previous studies [ 23 – 25 ], variation of the perturbation score values in the identified common network was generally consistent with expectations for cellular senescence. Interestingly, the gene expressions at the young and senescence stage were completely opposed.…”

“…Among the 207 cell cycle-related genes, only 14 continuously affected senescence while maintaining a constant topology and displaying gradual and directional changes in perturbation score values. During aging, we identified genes known to be up- and down-regulated [ 23 – 25 ] during senescence with similar regulations in our analysis. For example, KIF20, a cell cycle controller, was down-regulated in senescence status by activation of p16 via the Rb/E2F pathway [ 23 ]; CRABP2 was strongly down-regulated with increased passage number in human amniotic fluid-derived stem cells and might act as a negative regulator to limit cellular senescence [ 24 ]; and CCND1, another well-known cell cycle regulator, is down-regulated in HDF senescence [ 25 ].…”

IFNAR2-dependent gene expression profile induced by IFN-α in Pteropus alecto bat cells and impact of IFNAR2 knockout on virus infection

“…This is not found in other non-immune cells [ 33 , 36 ]. Genes related to DNA damage regulation were also induced, including CDKN1A, SP100, PML and SIRT1 [ 37 , 38 , 39 ].…”

Characterization of KIF20A as a prognostic biomarker and therapeutic target for different subtypes of breast cancer

“…The present study demonstrated the potential clinical application of KIF20A inhibition for breast cancer treatment by selectively inhibiting the ATPase activity of KIF20A and suppressing KIF20A expression using siRNAs. Breast cancer cells were treated with the KIF20A inhibitor, paprotrain, which reversibly blocks KIF20A function by being uncompetitive with ATP and noncompetitive with microtubules (45)(46)(47). Similar to si-KIF20A, paprotrain decreased the viability of the ZR-75-1 (Luminal A), SK-BR-3 (HER2/neu-positive) and HCC1937 (TNBC with BRCA1 mutation) breast cancer cell lines via G2/M arrest and subsequent mitotic cell death as monitored by live-cell imaging.…”