What is it about?
Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to methyl isocyanate (MIC), one of the most toxic isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and γ-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis.
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Why is it important?
As isocyanates comprise an industrially important group of chemicals, we aimed at listing the longitudinal effects of isocyanates on cell cycle regulation in liver epithelium. Here, we sequentially delineated the status of different proteins arbitrating the MIC induced deregulation of cell cycle in eliciting genomic instability in mouse liver epithelial (NCTC-1469) cells. Our study enlightens the oncogenic capability of MIC in NCTC-1469 cells with elevated DNA damage response proteins, deregulation of DNA damage checkpoint genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression. Further, the overexpression of cyclin A, cyclin E, CDK-2 proteins along with over-expression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations,and loss of Pot1a unveiled the inception of genomic instability in the treated cells. Thus, MIC impact s key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis.
Perspectives
I presume, further down-stream investigations could prove to be fundamental in determining the individual risks and help us in assortment of heritable genetic as well as epigenetic traits likely to be transmitted to future generations. Given the magnitude and implications of the tragedy, epidemiological investigations and human bio-monitoring should be the preferred study models. But, lack of knowledge of an established biomarker for a case such as Bhopal,augurs well for comparative work on cellular model systems to provide critical link in modeling the progressive consequences of dose-exposure relationships.
Dr Venkata GORANTLA RAGHURAM
Tata Memorial Centre
Read the Original
This page is a summary of: Cell cycle deregulation by methyl isocyanate: Implications in liver carcinogenesis, Environmental Toxicology, January 2012, Wiley,
DOI: 10.1002/tox.21757.
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