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The zinc finger transcription factor EGR-1 impedes interleukin-1-inducible tumor growth arrest
S F Sells1, S Muthukumar, V P Sukhatme
1Department of Surgery, University of Kentucky, Lexington 40536.
Abstract:
Interleukin-1 (IL-1) is a growth arrest signal for diverse human tumor cell lines. We report here that the action of this cytokine in melanoma cells is associated with induction of EGR-1, a zinc finger protein that activates gene transcription. Both growth arrest and EGR-1 are induced via the type I receptor of IL-1. To determine the role of EGR-1 in IL-1 action in melanoma cells, we used a chimera expressing the transrepression domain of the Wilm's tumor gene, WT1, and the DNA binding domain of Egr-1. This chimera competitively inhibited EGR-1-dependent transactivation via the GC-rich DNA binding sequence, indicating that it acted as a functional dominant negative mutant of Egr-1. Melanoma cell lines stably transfected with the dominant negative mutant construct were supersensitive to IL-1 and showed accelerated G0/G1 growth arrest compared with the parental cell line. The effect of the dominant negative mutant construct was mimicked by addition of an antisense Egr-1 oligomer to the culture medium of the parental cells: the oligomer inhibited EGR-1 expression and accelerated the growth-inhibitory response to IL-1. These data imply that EGR-1 acts to delay IL-1-mediated tumor growth arrest.
Insights
Interleukin-1 (IL-1) triggers tumor cell growth arrest by inducing EGR-1. However, EGR-1 delays this IL-1-mediated growth arrest in melanoma cells, suggesting it acts as a brake on tumor suppression.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Interleukin-1 (IL-1) functions as a growth arrest signal for various human tumor cell lines.
- The IL-1 type I receptor mediates IL-1's effects, including growth arrest and EGR-1 induction in melanoma cells.
Purpose of the Study:
- To elucidate the role of Early Growth Response-1 (EGR-1) in mediating the effects of IL-1 on melanoma cell growth.
- To investigate whether EGR-1 influences the timing or efficacy of IL-1-induced growth arrest.
Main Methods:
- Utilized a dominant-negative mutant chimera of EGR-1 (WT1 transrepression domain + Egr-1 DNA binding domain) to inhibit EGR-1 activity.
- Generated melanoma cell lines stably transfected with the dominant-negative EGR-1 construct.
- Administered antisense Egr-1 oligomers to parental melanoma cells to suppress EGR-1 expression.
Main Results:
- The dominant-negative EGR-1 mutant rendered melanoma cells supersensitive to IL-1, accelerating G0/G1 growth arrest.
- Antisense Egr-1 oligomers mimicked the effect of the dominant-negative mutant, inhibiting EGR-1 expression and enhancing IL-1's growth-inhibitory response.
- These findings indicate that EGR-1 actively delays the tumor growth arrest induced by IL-1.
Conclusions:
- EGR-1 plays a critical role in modulating the response of melanoma cells to IL-1.
- EGR-1 functions as a negative regulator, delaying IL-1-mediated tumor growth arrest.
- Targeting EGR-1 may represent a therapeutic strategy to enhance IL-1's anti-tumor effects in melanoma.