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Epidermal growth factor-induced growth inhibition requires Stat1 activation
1Laboratory of Cell Biology, The Rockefeller University, New York, New York 10021-6399, USA.
Abstract:
Epidermal growth factor (EGF) is a mitogen for most epithelial cells. Paradoxically, the growth of some cultured cell lines, containing high numbers of EGF receptors, are inhibited by EGF. Here we demonstrate that growth inhibition by EGF in several cell lines correlates with the activation of the signal transducer and activator of transcription (Stat) 1. In contrast, in normal fibroblasts and several cell lines that are growth stimulated by EGF, we observed no or very transient activation of Stat1. A causal association between Stat1 activation by EGF and growth inhibition was suggested by the expression of a dominant-negative Stat1 in A431 cells, resulting in the loss of Stat1 DNA binding and concomitant resistance to growth inhibition by EGF. We conclude that, in the cells examined, EGF-induced arrest of growth requires activated Stat1.
Insights
Epidermal growth factor (EGF) can paradoxically inhibit the growth of some cells. This study shows EGF-induced growth arrest requires the activation of signal transducer and activator of transcription 1 (Stat1).
Area of Science:
- Cell biology
- Molecular signaling
- Cancer research
Background:
- Epidermal growth factor (EGF) typically promotes cell proliferation.
- However, some cell lines exhibit growth inhibition in response to EGF, particularly those with abundant EGF receptors.
Purpose of the Study:
- To investigate the molecular mechanisms underlying EGF-induced growth inhibition.
- To determine the role of signal transducer and activator of transcription (Stat) proteins in this paradoxical response.
Main Methods:
- Cultured cell lines with varying responses to EGF were utilized.
- Activation of Stat1 by EGF was assessed.
- Dominant-negative Stat1 was expressed in A431 cells to evaluate its effect on EGF-induced growth inhibition and Stat1 DNA binding.
Main Results:
- EGF-induced growth inhibition in specific cell lines correlated with Stat1 activation.
- Normal fibroblasts and growth-stimulated cell lines showed minimal or transient Stat1 activation.
- Expression of dominant-negative Stat1 abolished Stat1 DNA binding and conferred resistance to EGF-induced growth inhibition.
Conclusions:
- Activated Stat1 is a critical mediator of EGF-induced growth arrest in the studied cell lines.
- This finding elucidates a specific signaling pathway through which EGF can exert opposing effects on cell growth.