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) (5-100μM) 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.