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Cited by 51Heavy Metal Exposure and ToxicityCarcinogens and Genotoxicity AssessmentDNA Repair Mechanisms

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

Lin, Y.-W.·2003·Carcinogenesis
DOI 10.1093/carcin/24.1.53
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Abstract

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 micro M) 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.

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  1. IARC (1987) Overall evaluation of carcinogenicity: an updating of IARC monographs. In IARC Monographs on the Evaluation of Carcinogenic Risks to Human, Volumes 1-42, Supplement 7. International Agency for Research on Cancer, Lyon, pp. 230-232.

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Authors
Lin, Y.-W.
Affiliations
National Tsing Hua University (TW)
Corresponding author
Lin, Y.-W.
ORCID
Lin, Y.-W.
Venue
Carcinogenesis
Publisher
Oxford University Press (OUP)
Published
2003-01-01
Volume
24
Issue
1
Pages
53-61
ISSN
  • 0143-3334 (ISSN-L)
  • 1460-2180
DOI
10.1093/carcin/24.1.53
OpenAlex
W2167539266
Cited by
51
References
67
Citations by year
2025: 1 · 2024: 1 · 2021: 3 · 2019: 1 · 2018: 1 · 2017: 6 · 2015: 2 · 2014: 3 · 2013: 2
FWCI
2.60
Type
journal article
Language
en
Open access
closed
Locations
  • Carcinogenesis (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Taiwan University Hospital
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
lead acetate, ERK signaling, nucleotide excision repair, mutagenicity, cytotoxicity, Akt signaling, MAPK signaling, PD98059, HPRT mutations, fibroblasts, DNA repair
MeSH terms
Cell Division, DNA Repair, Enzyme Activation, Enzyme Inhibitors, Flavonoids, Humans, Organometallic Compounds, Phosphorylation, Proto-Oncogene Proteins, Tumor Cells, Cultured, Mutagenesis, Proto-Oncogene Proteins c-fos, Protein Serine-Threonine Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Proto-Oncogene Proteins c-akt

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