Abstract
The Ras-cyclic AMP pathway is connected to other nutrient-regulated signaling pathways and mediates the global stress responses of Saccharomyces cerevisiae. Here, we show that Rom2p, the Rho1 GTP/GDP exchange factor, can mediate stress responses and cell growth via the Ras-cAMP pathways. ROM2 was isolated as a suppresser of heat and NaCl sensitivity caused by the lack of the Ras-GTPase activator Ira2p or of cAMP phosphodiesterases. Subsequent analysis of strains with a rom2 deletion showed that Rom2p is essential for resistance to a variety of stresses caused by freeze-thawing, oxidants, cycloheximide, NaCl, or cobalt ions. Stress sensitivity and the growth defect caused by the rom2 deletion could be suppressed by depleting Ras or protein kinase A (PKA) activity or by overexpressing the high affinity cAMP phosphodiesterase Pde2p. In addition, overexpression of ROM2 could not rescue cells lacking the regulatory subunit of PKA, indicating that the Ras-adenylate, cyclase-PKA cascade is essential for Rom2p-mediated stress responses and cell growth. Deletion of IRA2 exacerbated the freeze-thaw sensitivity and growth defect of the rom2 mutant, indicating that Rom2p signaling may control Ras independently of IRA2. Increases in cAMP levels were detected in the rom2 deletion mutants, and these were comparable with the effects of an ira2 mutation. The effects of the deletion of ROM2 on sensitivity to hydrogen peroxide, paraquat, and cobalt ions, but not to caffeine, were reduced when a constitutive allele of RHO1 was introduced on a single copy plasmid. However, the effects of the deletion of ROM2 on sensitivity to diamide and NaCl were exacerbated. Taken together, our data indicate that Rom2p can regulate PKA activity by controlling cAMP levels via the Ras-cAMP pathway and that for those stresses related to oxidative stress, this cross-talk is probably mediated via the Rho1p-activated MAPK pathway.
Highlights
The ability of cells to appropriately respond to alterations in environment is essential for the survival of stress situations, and processes for stress sensing and the subsequent modulation of cell physiology require the involvement of signal transduction pathways
Isolation of ROM2 as a Stress Defense Gene—IRA2 and PDE2 are important genes encoding components of the RascAMP signaling pathway that are important in maintaining resistance to a wide range of stress conditions [49]
ROM2 overexpression could suppress heat shock sensitivity caused by the lack of cAMP phosphodiesterase activity in the pde1 pde2 double mutant, but it could not effectively rescue yeast cells lacking BCY1, which encodes the regulatory subunit of protein kinase A (PKA) (Fig. 1B)
Summary
Yamamoto the cross-talk between Rom2p and the Ras-cAMP pathway. We show that the sensitivities to various stresses and the growth defect caused by rom deletion can be suppressed by modulating activity of the Ras-cAMP pathway. We show that Rom2p can control cAMP levels in the wild-type strain. Our study demonstrates that Rom2p can mediate negative regulation of the Ras-cAMP signal transduction pathway
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