Journal Article

Persistent activation of ERK1/2 by lead acetate increases nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity

Yun-Wei Lin, Show-Mei Chuang and Jia-Ling Yang

in Carcinogenesis

Volume 24, issue 1, pages 53-61
Published in print January 2003 | ISSN: 0143-3334
Published online January 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/24.1.53
Persistent activation of ERK1/2 by lead acetate increases nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity

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Lead, a possible human carcinogen, affects signal transduction pathways in many aspects, yet exhibits low mutagenicity in human cells. In this study, we explore whether signaling pathways including the four MAPKs and AKT affect DNA repair and mutagenicity in the exposure of mammalian cells to lead acetate [Pb(II)]. Pb(II) increased the phosphorylated ERK1/2 and phosphorylated AKT but not the phosphorylated ERK5, phosphorylated p38 and JNK activity in human non-small cell lung adenocarcinoma CL3 cells. The duration of ERK1/2 activation was much longer than AKT activation and these two signals were independently activated by Pb(II) in CL3 cells. Intriguingly, a MKK1/2 inhibitor PD98059 (25–50 μM) markedly suppressed ERK1/2 activation and greatly promoted the hprt mutation frequency and cytotoxicity in Pb(II)-treated CL3 cells. Conversely, inhibition of the AKT signal by wortmannin did not exhibit such effects. Inhibition of the persistently activated ERK1/2 in Pb(II)-treated diploid human fibroblasts by PD98059 also markedly increased the mutagenicity and cytotoxicity. The Pb(II)-induced mutagenicity and cytotoxicity were significantly higher in nucleotide excision repair (NER)-deficient UVL-10 rodent cells than their counterpart AT3-2 cells; also, ERK1/2 activation by Pb(II) was observed in AT3-2 but not UVL-10 cells. Furthermore, cellular NER synthesis was enhanced by Pb(II) exposure, which was markedly suppressed by PD98059. Activation of ERK1/2 by expressing a constitutively active form of MKK1 in CL3 cells also elevated cellular NER synthesis. Together, these results indicate that persistent activation of ERK1/2 signaling by Pb(II) enhances cellular NER synthesis, thereby conferring anti-cytotoxicity and anti-mutagenicity.

Keywords: ERK, extracellular signal-regulated kinase; ICP-MS, inductively coupled plasma-mass spectrometer; JNK, c-JUN N-terminal kinase; MAPK, mitogen-activation protein kinase; MKK, MAPK kinase; MKKK, MKK kinase; NER, nucleotide excision repair; Pb(II), lead acetate; PBS, phosphate-buffered saline; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; 6-TG, 6-thioguanine; WCE, whole cell extract

Journal Article.  7875 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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