Journal Article

Short-term depletion of catalase suppresses cadmium-elicited c-Jun N-terminal kinase activation and apoptosis: role of protein phosphatases

Show-Mei Chuang, I-Ching Wang, Yi-Shi Hwua and Jia-Ling Yang

in Carcinogenesis

Volume 24, issue 1, pages 7-15
Published in print January 2003 | ISSN: 0143-3334
Published online January 2003 | e-ISSN: 1460-2180 | DOI:
Short-term depletion of catalase suppresses cadmium-elicited c-Jun N-terminal kinase activation and apoptosis: role of protein phosphatases

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The c-Jun N-terminal kinase (JNK) is a vital stress-activated signal that can be regulated differentially under oxidant or antioxidant conditions. Recently, we have reported that activation of JNK by cadmium chloride (Cd) contributes to apoptosis in CL3 human lung adenocarcinoma cells. Although oxidative stress has been implicated in numerous biochemical effects altered by Cd, its role in Cd-elicited JNK activation has not been established. Here we report that catalase is crucial for the activation of JNK by Cd. Short-term treatment of 3-amino-1,2,4-triazole (3AT), a specific catalase inhibitor, completely suppressed the Cd-elicited JNK activation, conversely, exogenous addition of catalase increased the intensity and duration of JNK activation in Cd-treated CL3 cells. Co-administering high doses of H2O2 (500–1000 μM) with Cd also markedly decreased JNK activity, although at doses <200 μM H2O2 enhanced the Cd-elicited JNK activation in CL3 cells. 3AT also blocked JNK activation in Cd-treated normal human fibroblasts and Chinese hamster ovary cells, and in UV-irradiated CL3 cells. However, mannitol, a hydroxyl radical scavenger, did not alter the JNK activity in Cd-treated human and rodent cells. Intriguingly, sodium fluoride or okadaic acid, inhibitors for serine/threonine protein phosphatases (PP), recovered the JNK activity in CL3 cells exposed to Cd plus 3AT; however, the protein tyrosine phosphatases inhibitor sodium orthovanadate did not. Furthermore, 3AT decreased but catalase increased the Cd-induced cytotoxicity, apoptosis and procaspase-3 degradation in CL3 cells. Together, these results indicate that persistent activation of apoptotic JNK signal by Cd requires functional catalase and that short-term depletion of catalase activity may facilitate okadaic acid-sensitive PP to down-regulate the JNK activation and may predispose these cells to carcinogenic transformation upon Cd exposure.

Keywords: 3AT, 3-amino-1,2,4-triazole; Cd, cadmium; CHO-K1, Chinese hamster ovary-K1; FITC, fluorescein isothiocyanate; GST, glutathione S-transferase π; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; MKKK, MKK kinase; MKP, dual-specificity MAPK phosphatase; PBS, phosphate-buffered saline; PP, serine/threonine protein phosphatase; PP2Ac, catalytic subunit of PP2A; PTP, protein tyrosine phosphatase; ROS, reactive oxygen species; WCE, whole cell extract

Journal Article.  7281 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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