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Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappaB
D O Henry1, S A Moskalenko, K J Kaur
1Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75235, USA.
Abstract:
Ral GTPases have been implicated as mediators of Ras-induced signal transduction from observations that Ral-specific guanine nucleotide exchange factors associate with Ras and are activated by Ras. The cellular role of Ral family proteins is unclear, as is the contribution that Ral may make to Ras-dependent signaling. Here we show that expression of activated Ral in quiescent rodent fibroblasts is sufficient to induce activation of NF-kappaB-dependent gene expression and cyclin D1 transcription, two key convergence points for mitogenic and survival signaling. The regulation of cyclin D1 transcription by Ral is dependent on NF-kappaB activation and is mediated through an NF-kappaB binding site in the cyclin D1 promoter. Ral activation of these responses is likely through an as yet uncharacterized effector pathway, as we find activation of NF-kappaB and the cyclin D1 promoter by Ral is independent of association of Ral with active phospholipase D1 or Ral-binding protein 1, two proteins proposed to mediate Ral function in cells.
Insights
Activated Ral GTPase signaling induces NF-kappaB-dependent gene expression and cyclin D1 transcription. This Ral pathway activation is independent of known Ral effectors, suggesting a novel mechanism in Ras-mediated signaling.
Area of Science:
- Cellular biology
- Molecular signaling
- Signal transduction pathways
Background:
- Ral GTPases are implicated in Ras-induced signal transduction.
- The precise cellular roles and contributions of Ral proteins to Ras signaling remain unclear.
Purpose of the Study:
- To investigate the cellular functions of Ral GTPases.
- To determine the contribution of Ral to Ras-dependent signaling pathways.
Main Methods:
- Expression of activated Ral in quiescent rodent fibroblasts.
- Analysis of NF-kappaB-dependent gene expression.
- Assessment of cyclin D1 transcription.
- Investigation of Ral interactions with phospholipase D1 and Ral-binding protein 1.
Main Results:
- Activated Ral expression is sufficient to induce NF-kappaB-dependent gene expression.
- Activated Ral induces cyclin D1 transcription via an NF-kappaB binding site.
- Ral activation of these pathways is independent of phospholipase D1 and Ral-binding protein 1.
Conclusions:
- Ral GTPases play a significant role in regulating gene expression and cell cycle progression.
- Ral activation of NF-kappaB and cyclin D1 transcription likely occurs through an uncharacterized effector pathway.
- These findings suggest a novel mechanism for Ral-mediated signaling in Ras-dependent cellular processes.