Opposed arsenite-mediated regulation of p53-survivin is involved in neoplastic transformation, DNA damage, or apoptosis in human keratinocytes.
Biphasic dose-response relationship induced by environmental agents is often characterized with the effect of low-dose stimulation and high dose inhibition. Some studies showed that arsenite may induce cell proliferation and apoptosis via biphasic dose-response relationship in human cells; however, mechanisms underlying this phenomenon are not well understood. Our present study shows that, for human keratinocytes (HaCaT) cells, a low concentration of arsenite activates extracellular signal-regulated kinases (ERKs), which leads to up-regulation of nuclear factor κB (NF-κB) binding to DNA and to elevated, NF-κB-dependent expression of mot-2 (a p53 inhibitor) and survivin (an inhibitor of apoptosis). Activation of p53 is blocked, and neoplastic transformation is enhanced. Inhibition of ERKs reduces cell proliferation and neoplastic transformation. In contrast, a high concentration of arsenite activates c-Jun N-terminal kinases (JNKs), positive regulators of p53, by binding to p53 and preventing its murine double minute 2 (mdm2)-mediated degradation. The elevated levels of p53 lead to repair of DNA damage and apoptosis. Inhibition of JNKs increases DNA damage but decreases apoptosis. By identifying a mechanism whereby ERKs and JNKs-mediated regulation of the p53-survivin signal pathway is involved in the biphasic effects of arsenite on human keratinocytes, our data expand understanding of arsenite-induced cell proliferation, neoplastic transformation, DNA damage, and apoptosis.
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
Yuan
Y
Li
Rongrong
R
Jiang
Yue
Y
Zhao
Yuan
Y
Xu
Min
M
Ling
Ying
Y
Pang
Lu
L
Shen
Yun
Y
Zhou
Jianping
J
Zhang
Jianwei
J
Zhou
Xinru
X
Wang
Qizhan
Q
Liu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000633:toxicity*; D026501:Blotting, Southwestern; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis*; D015603:Keratinocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009369:Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D017670:Sodium Compounds / Q000633:toxicity*; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D018053:Arsenites; C107489:BIRC5 protein, human; D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D017670:Sodium Compounds; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C017947:sodium arsenite