ToxSci Advance Access originally published online on June 12, 2007
Toxicological Sciences 2007 99(1):126-140; doi:10.1093/toxsci/kfm153
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p53 Response to Arsenic Exposure in Epithelial Cells: Protein Kinase B/Akt Involvement
* Departamento de Genética y Biología Molecular
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México
Laboratorio de Citopatología, Unidad Académica de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, México
Departamento de Genética y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, UNAM, México D.F., México
1 To whom correspondence should be addressed at Departamento de Genética y Biología Molecular, Cinvestav-IPN, Apartado Postal 14-740 México DF 07000, México. Fax: +52-55-5061-3800 ext. 5380. E-mail: ebayghen{at}cinvestav.mx.
Received February 9, 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 phosphatidyl inositol 3-kinase (PI3K)/Ca2+/diacylglicerol dependent protein kinase/protein kinase B (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/glycogen synthase kinase-3 beta 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.