title: Tl(I) and Tl(III) alter the expression of EGF-dependent signals and cyclins required for pheochromocytoma (PC12) cell-cycle resumption and progression.
abstract: The effects of thallium [Tl(I) and Tl(III)] on the PC12 cell cycle were evaluated without (EGF(-)) or with (EGF(+)) media supplementation with epidermal growth factor (EGF). The following markers of cell-cycle phases were analyzed: cyclin D1 (G1 ); E2F-1, cyclin E and cytosolic p21 (G1 →S transition); nuclear PCNA and cyclin A (S); and cyclin B1 (G2). The amount of cells in each phase and the activation of the signaling cascade triggered by EGF were also analyzed. Tl(I) and Tl(III) (5-100 μM) caused dissimilar effects on PC12 cell proliferation. In EGF(-) cells, Tl(I) increased the expression of G1 →S transition markers and nuclear PCNA, without affecting cyclin A or cyclin B1. In addition to those, cyclin B1 was also increased in EGF(+) cells. In EGF(-) cells, Tl(III) increased the expression of cyclin D1, all the G1→S and S phase markers and cyclin B1. In EGF(+) cells, Tl(III) increased cyclin D1 expression and decreased all the markers of G1 →S transition and the S phase. Even when these cations did not induce the activation of EGF receptor (EGFR) in EGF(-) cells, they promoted the phosphorylation of ERK1/2 and Akt. In the presence of EGF, the cations anticipated EGFR phosphorylation without affecting the kinetics of EGF-dependent ERK1/2 and Akt phosphorylation. Altogether, results indicate that Tl(I) promoted cell proliferation in both EGF(-) and EGF(+) cells. In contrast, Tl(III) promoted the proliferation of EGF(-) cells but delayed it in EGF(+) cells, which may be related to the toxic effects of this cation in PC12 cells.
authors.affiliation: Department of Biological Chemistry, IQUIFIB (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, C1113AAD, Buenos Aires, Argentina.
authors.forename: María T L
authors.initials: MT
authors.lastname: Pino
authors.affiliation: Department of Biological Chemistry, IQUIFIB (UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, C1113AAD, Buenos Aires, Argentina.
authors.forename: Sandra V
authors.initials: SV
authors.lastname: Verstraeten
mesh_terms: D000818:Animals; D002412:Cations; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D016213:Cyclins / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000187:drug effects*; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000235:genetics; D010084:Oxidation-Reduction; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014025:Titanium / Q000633:toxicity*
chemical_list: D002412:Cations; D018797:Cell Cycle Proteins; D016213:Cyclins; D004815:Epidermal Growth Factor; D014025:Titanium; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt
keywords: cell cycle; cell signaling; cyclins; epidermal growth factor; thallium