title: p53 response to arsenic exposure in epithelial cells: protein kinase B/Akt involvement.
abstract: 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.
authors.affiliation: Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico.
authors.forename: Marisol
authors.initials: M
authors.lastname: Sandoval
authors.forename: Moisés
authors.initials: M
authors.lastname: Morales
authors.forename: Rocío
authors.initials: R
authors.lastname: Tapia
authors.forename: Luz
authors.initials: L
authors.lastname: del Carmen Alarcón
authors.forename: Montserrat
authors.initials: M
authors.lastname: Sordo
authors.forename: Patricia
authors.initials: P
authors.lastname: Ostrosky-Wegman
authors.forename: Arturo
authors.initials: A
authors.lastname: Ortega
authors.forename: Esther
authors.initials: E
authors.lastname: López-Bayghen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D018053:Arsenites / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003571:Cytochalasin B / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004785:Environmental Pollutants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D017670:Sodium Compounds / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D018053:Arsenites; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; D003571:Cytochalasin B; C017947:sodium arsenite; D051057:Proto-Oncogene Proteins c-akt