ToxSci Advance Access published online on June 12, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm153
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p53 Response to Arsenic Exposure in Epithelial Cells: Protein Kinase B/Akt Involvement
1 Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México 2 Departamento de Genética y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, UNAM, México D.F., México 3 Laboratorio de Citopatología, Unidad Académica de Ciencias Químico Biológicas. Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, México 4 Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México
Correspondence:, Esther López-Bayghen, Ph.D., Departamento de Genética y Biología Molecular, Cinvestav-IPN, Apartado Postal 14-740 México DF 07000, México, Phone 52 55 5061 3340, Fax 52 55 5061 3800 x 5380, E-mail: ebayghen{at}cinvestav.mx
Received February 9, 2007; revision received June 6, 2007; accepted June 6, 2007
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Abstract |
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Inorganic arsenic is a major environmental contaminant associated with an increased risk of human skin cancer. Arsenic modulates cellular signaling pathways that affect diverse processes such as cell proliferation, differentiation and apoptosis, including genotoxic damage. The p53 protein plays a central role in mediating stress and DNA damage responses, leading to either growth arrest or apoptosis. Several signal transduction pathways activated under a plethora of stressing conditions increase p53 protein levels. To further understand the molecular mechanisms involved in the arsenic mode of action, we explored the effects of this metalloid on the activation of the PI3K/PKC/PKB signaling cascade and its repercussion in p53 activation in two epithelial cell types: primary normal human keratinocytes cultures (NHK) and the carcinoma-derived C33-A cell line. Although in both cell systems arsenic leads to an increase in p53 and its binding to DNA, the final outcome is different. In NHK, arsenic triggers a sustained activation of the PI3K/PKB/GSK-3ß pathway, driving the cell into a cell-differentiated stage in which the proliferation signals are turned down. In sharp contrast, in C33-A cells, arsenic leads to a transient increase in p53 followed by a drastic reduction in its nuclear levels and an increase in cell proliferation. These findings favor the notion that p53-stage and transcriptional abilities are important to understand modifications in the proliferation-differentiation balance, an equilibrium that is severely impaired by arsenic.
Key Words: arsenic; p53 protein; Protein Kinase B; Akt; human keratinocytes.