Abstract
Small GTPases of the Rho family play a central role in cellular processes that involve the reorganization of the actin-based cytoskeleton. Rho-related GTPases, which include Rac and Cdc42, can also regulate gene expression often through the activation of kinase cascades leading to enhanced activity of stress activated protein kinases (SAPKs), including JNK and p38 MAP kinases. As SAPKs are implicated in programmed cell death, these observations suggest that Rho GTPases may promote the initiation of the apoptotic process. However, recent reports suggest that Rho GTPases can have either a protective or a pro-apoptotic role, depending on the particular cellular context. In an effort to explore the molecular mechanisms underlying these divergent biological activities, we asked whether there was indeed a correlation between the ability to induce SAPKs and apoptosis by Rho family members. We found that although constitutively activated (Q61L) mutants of Rac1, Cdc42, and RhoG, a Rac1 related GTPase of unknown function, potently induce JNK in COS 7 cells, none of these GTPases could induce apoptosis, nor enhance uv-induced cell death. In contrast, Rac1 and RhoG efficiently protected cells from uv-induced apoptosis. Furthermore, we provide evidence that Rac1 and RhoG can activate both apoptotic and anti-apoptotic pathways. Whereas the former is mediated through JNK, the latter is independent on the transcriptional activation of NF-κB, a pro-survival pathway, but results from the direct interaction of these GTPases with phosphatidylinositol 3-kinase (PI3K) and the stimulation of Akt. Together, these findings indicate that members of the Rho family of small GTP-binding proteins can provoke the concomitant stimulation of two counteracting signaling pathways, and that their balance ultimately determines the ability of these GTPases to promote cell survival or death.
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Abbreviations
- DMSO:
-
dimethyl sulfoxide
- FITC:
-
fluorescein isotiocyanate
- GFP:
-
green fluorescent protein
- HA:
-
hemagglutinin epitope tag
- HRP:
-
horseradish peroxidase
- H2B:
-
histone 2B
- JNK:
-
c-jun N-terminal kinase
- MAP kinase:
-
mitogen activated protein kinase
- MBP:
-
myelin basic protein
- ONPG:
-
o-nitrophenyl β-D-galactopyranoside; PBS-phosphate buffered saline
- PI3K:
-
phosphatidylinositol-3-OH kinase
- PVDF:
-
polyvinylidene fluoride
- s.e.m.:
-
standard error of the mean
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Acknowledgements
We are especially grateful to C DeGraff and E Powell for excellent secretarial assistance. We thank Dr Siebenlist for providing the construct for h-IκBα S32G S36A, Dr Lenardo for the vector containing FLICE and Dr Davis for the kind gift of JIP-1 expression plasmids. Thanks to Dr Montaner and Dr Servitja for their critical reading of the manuscript.
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Murga, C., Zohar, M., Teramoto, H. et al. Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-κB. Oncogene 21, 207–216 (2002). https://doi.org/10.1038/sj.onc.1205036
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DOI: https://doi.org/10.1038/sj.onc.1205036
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