Zinc induces ERK-dependent cell death through a specific Ras isoform
Claudette Klein1, Kimberly Creach, Virginia Irintcheva
1Department of Biochemistry and Molecular Biology, School of Medicine, Saint Louis University, Saint Louis, MO, USA. kleinc@slu.edu
Apoptosis : an International Journal on Programmed Cell Death
|October 3, 2006
Summary
Zinc ions trigger apoptosis in embryonic fibroblasts, even without p53. This cell death pathway is ERK-dependent and specifically involves H-Ras activation, offering new insights into zinc
Area of Science:
- Cell Biology
- Biochemistry
- Toxicology
Background:
- p53 is a key tumor suppressor involved in cell death.
- Zinc's role in cell death mechanisms is not fully understood.
- Apoptosis can occur through p53-dependent or p53-independent pathways.
Purpose of the Study:
- To investigate the mechanism of zinc-induced cell death in p53-deficient cells.
- To determine the role of the Ras/ERK pathway in zinc-mediated apoptosis.
- To identify the specific Ras isoform activated by zinc.
Main Methods:
- Utilized IIC9 embryonic fibroblasts (p53-minus).
- Administered zinc and the ionophore pyrithione to induce cell death.
- Assessed apoptosis using relevant assays.
- Investigated the Ras/ERK signaling pathway, including dominant-negative Ras expression and Raf-RBD pull-down assays.
Main Results:
- Zinc induces apoptosis in p53-minus IIC9 cells.
- The cell death pathway is dependent on ERK activation.
- Zinc treatment specifically activates H-Ras, not N-Ras.
- Dominant-negative Ras expression inhibits zinc-induced ERK activation and cytotoxicity.
Conclusions:
- Intracellular zinc initiates a p53-independent apoptotic response.
- Zinc-mediated cell death relies on the activation of the Ras/ERK pathway.
- H-Ras isoform specificity distinguishes zinc-induced Ras activation from other stimuli.
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