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Zinc induces ERK-dependent cell death through a specific Ras isoform

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Abstract

The effect of Zn on p53-independent cell death was examined in IIC9 embryonic fibroblasts. Despite the fact that these cells are p53-minus, Zn-mediated death occurs via an apoptotic mechanism. Death is facilitated by the presence of the Zn ionophore, pyrithione, indicating that intracellular Zn initiates the death response. Our investigations of the mechanism of Zn action demonstrate that Zn induces the death of IIC9 cells in a manner that is ERK-dependent. Expression of dn-(dominant negative)Ras attenuates ERK1/2 activation by Zn, and correspondingly reduces its cytotoxic effects. Raf-RBD pull-down experiments confirm that Zn treatment activates Ras and identified H-Ras as the specific isoform activated. This contrasts the activation of N-Ras that occurs when IIC9 cells are stimulated with thrombin. Thus, although the prolonged activation of the Ras/ERK pathway by Zn is similar to that seen when induced by mitogen, the distinguishing feature appears to be the isoform specificity of Ras activation.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, Saint Louis, MO

    Claudette Klein, Katherine J. Hughes, Penny Lane Blackwell & John A. Corbett

  2. Department of Pharmacological and Physiological Science, School of Medicine, Saint Louis University, Saint Louis, MO

    Virginia Irintcheva & Joseph J. Baldassare

  3. St. Louis University School of Medicine, St. Louis, MO

    Kimberly Creach

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  1. Claudette Klein
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  2. Kimberly Creach
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  3. Virginia Irintcheva
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  4. Katherine J. Hughes
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  5. Penny Lane Blackwell
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  6. John A. Corbett
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  7. Joseph J. Baldassare
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Correspondence to Claudette Klein.

Additional information

This work was supported by National Institute of Health Grants DK-52194 and AI-44458 (to J.A.C). P.L Blackwell was supported by an American Heart Association Grant in Aid 0555574Z (to C.K), K.J. Hughes was supported by the National Institute of Health Training Grant (GM008306) and Kimberly Creach was supported by St. Louis University Medical School Summer Research Fellowship.

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Klein, C., Creach, K., Irintcheva, V. et al. Zinc induces ERK-dependent cell death through a specific Ras isoform. Apoptosis 11, 1933–1944 (2006). https://doi.org/10.1007/s10495-006-0089-6

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