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Differential programming of p53-deficient embryonic cells during rotenone block
Citation:
GREEN, M. L., A. V. SINGH, L. RUEST, MICHELE M. PISANO, R. A. PROUGH, AND T. B. KNUDSEN. Differential programming of p53-deficient embryonic cells during rotenone block. TOXICOLOGY. Elsevier Ireland Limited, Limerick, Ireland, 290(1):31-41, (2011).
Impact/Purpose:
Our data not only showed p53 loss influences mitochondrial activity (metabolism), but conversely, mitochondrial stress directly influences p53 localization and function. Together this information suggests that the p53 molecule has an intimate relationship with the mitochondrial organelle such that their interaction allows the cell to compensate and adapt to stress in order to continue healthy growth and development of the whole embryo. The conceptual model also supports the notion that mitochondrial dysfunction and redistribution depends upon an intact microtubule network (Richter-Landsberg, 2001) that is independent of p53 and may be mediated by MAP kinase signaling. A large-scale mitochondrial screening compendium uncovered a link between microtubule disruption and an increase in the expression of genes for mitochondrial oxidative phosphorylation while suppressing ROS (Wagner et al., 2008). Further understanding of pathways regulated by specific mRNA and miRNA interactions may give us insight into how mitochondrial dysfunction influences p53 activity in developing embryonic tissues.
Description:
Mitochondrial dysfunction has been implicated in chemical toxicities. The present study used an in vitro model to investigate the differential expression of metabolic pathways during cellular stress in p53- efficient embryonic fibroblasts compared to p53-deficient cells. These cell lines differed with respect to NADH/NAD+ balance. This ratio constitutes a driving force for NAD- and NADH-dependent reactions and is inversed upon exposure to Rotenone (complex I inhibitor). Rotenone perturbed the structure of the elongated fibrillar tubulin network and decreased mRNA expression of tubulin genes both suggesting reprogramming and reorganization of the cytoskeleton in both cell lines. These changes were reflected in the abundance of specific mRNA and microRNA (miRNA) species as determined from genome-based analysis. Changes in mRNA and miRNA expression profiles reflected differences in energy utilizing pathways, consistent with the notion that the p53 pathway influences the cellular response to mitochondrial dysfunction and that at least some control may be embedded within specific mRNA/miRNA networks in embryonic cells.
