Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function

Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America.
PLoS Biology (Impact Factor: 9.34). 03/2007; 5(2):e35. DOI: 10.1371/journal.pbio.0050035
Source: PubMed

ABSTRACT Identification of common mechanistic principles that shed light on the action of the many chemically diverse toxicants to which we are exposed is of central importance in understanding how toxicants disrupt normal cellular function and in developing more effective means of protecting against such effects. Of particular importance is identifying mechanisms operative at environmentally relevant toxicant exposure levels. Chemically diverse toxicants exhibit striking convergence, at environmentally relevant exposure levels, on pathway-specific disruption of receptor tyrosine kinase (RTK) signaling required for cell division in central nervous system (CNS) progenitor cells. Relatively small toxicant-induced increases in oxidative status are associated with Fyn kinase activation, leading to secondary activation of the c-Cbl ubiquitin ligase. Fyn/c-Cbl pathway activation by these pro-oxidative changes causes specific reductions, in vitro and in vivo, in levels of the c-Cbl target platelet-derived growth factor receptor-alpha and other c-Cbl targets, but not of the TrkC RTK (which is not a c-Cbl target). Sequential Fyn and c-Cbl activation, with consequent pathway-specific suppression of RTK signaling, is induced by levels of methylmercury and lead that affect large segments of the population, as well as by paraquat, an organic herbicide. Our results identify a novel regulatory pathway of oxidant-mediated Fyn/c-Cbl activation as a shared mechanism of action of chemically diverse toxicants at environmentally relevant levels, and as a means by which increased oxidative status may disrupt mitogenic signaling. These results provide one of a small number of general mechanistic principles in toxicology, and the only such principle integrating toxicology, precursor cell biology, redox biology, and signaling pathway analysis in a predictive framework of broad potential relevance to the understanding of pro-oxidant-mediated disruption of normal development.

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Available from: Mark Noble, Sep 25, 2015
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    • "Interestingly , apoptotic-related signals caused by MeHginduced oxidative stress can be reversed by antioxidants such as N-acetylcysteine (NAC), glutathione (GSH), and glycine (Cuello et al. 2010; Lu et al. 2011; Pal et al. 2011). Also the activation of the enzyme Fyn kinase through MeHg-induced oxidative stress (0.02 lM), which finally affects diverse processes among them cell proliferation, survival, and differentiation, is effectively prevented by NAC (Li et al. 2007). "
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    ABSTRACT: There are considerable gaps in our knowledge on cell biological effects induced by the heavy metals mercury (Hg) and lead (Pb). In the present study we aimed to explore the effects of these toxicants on proliferation and cell size of primary human amniotic fluid stem (AFS) cells. Monoclonal human AFS cells were incubated with three dosages of Hg and Pb (single and combined treatment; ranging from physiological to cytotoxic concentrations) and the intracellular Hg and Pb concentrations were analyzed, respectively. At different days of incubation the effects of Hg and Pb on proliferation, cell size, apoptosis, and expression of cyclins and the cyclin-dependent kinase inhibitor p27 were investigated. Whereas we found Hg to trigger pronounced effects on proliferation of human AFS cells already at low concentrations, anti-proliferative effects of Pb could only be detected at high concentrations. Exposure to high dose of Hg induced pronounced downregulation of cyclin A confirming the anti-proliferative effects observed for Hg. Co-exposure to Hg and Pb did not cause additive effects on proliferation and size of AFS cells, and on cyclin A expression. Our here presented data provide evidence that the different toxicological effects of Pb and Hg on primary human stem cells are due to different intracellular accumulation levels of these two toxicants. These findings allow new insights into the functional consequences of Pb and Hg for mammalian stem cells and into the cell biological behavior of AFS cells in response to toxicants.
    Amino Acids 11/2011; 43(2):937-49. DOI:10.1007/s00726-011-1154-1 · 3.29 Impact Factor
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    • "Reports of such effects increased dramatically during the 20th Century commensurate with the increase in the production of synthetic chemicals – especially those derived from petroleum and natural gas (Gross, 2007). Many of these agents appear to induce defects manifest particularly in the nervous system (Li et al., 2007; Phelps, 2007). More recently, there has been significant focus on adverse cellular effects caused by oxidative stress, especially due to the actions of reactive oxygen species (ROS). "
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    ABSTRACT: The environment is a well-established source of damaging or disrupting influences on cellular function. In the past, studies of the mechanisms by which such disruptions occur have focused largely on either direct toxic effects on cellular function at the protein or cell signaling level, or mutagenic effects that impact the genome. In recent years there has been a growing appreciation for the potential for environmental influences to disrupt the epigenome and mechanisms of epigenetic regulation within the cell. Indeed, because of the inherent lability of the epigenome, this represents a primary target for environmentally induced disruption. This review summarizes the manner in which the epigenome normally regulates cellular function, the effects of disruptions on this function, and the manner in which such disruptions may or may not be corrected within the organism and/or transmitted to subsequent generations.
    Molecular and Cellular Endocrinology 09/2011; 354(1-2):9-15. DOI:10.1016/j.mce.2011.09.014 · 4.41 Impact Factor
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    • "See also Figures S1A–S1C. observed with O-2A progenitors (Smith et al., 2000; Power et al., 2002; Li et al., 2007), we have found that a decrease in normal cellular ROS levels can have an unexpectedly negative impact on self-renewal and neurogenesis both in vitro and in vivo. We observed a higher level of endogenous ROS in NSCs and within the neural stem cell niche, the SVZ, in vivo. "
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    ABSTRACT: The majority of research on reactive oxygen species (ROS) has focused on their cellular toxicities. Stem cells generally have been thought to maintain low levels of ROS as a protection against these processes. However, recent studies suggest that ROS can also play roles as second messengers, activating normal cellular processes. Here, we investigated ROS function in primary brain-derived neural progenitors. Somewhat surprisingly, we found that proliferative, self-renewing multipotent neural progenitors with the phenotypic characteristics of neural stem cells (NSC) maintained a high ROS status and were highly responsive to ROS stimulation. ROS-mediated enhancements in self-renewal and neurogenesis were dependent on PI3K/Akt signaling. Pharmacological or genetic manipulations that diminished cellular ROS levels also interfered with normal NSC and/or multipotent progenitor function both in vitro and in vivo. This study has identified a redox-mediated regulatory mechanism of NSC function that may have significant implications for brain injury, disease, and repair.
    Cell stem cell 01/2011; 8(1):59-71. DOI:10.1016/j.stem.2010.11.028 · 22.27 Impact Factor
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