Disease relevance of RAS1

• RAS1, on the other hand, appears to have a role in signaling life extension induced by transient, mild heat stress, which is distinct from its life-span-curtailing effect in the absence of stress and its lack of involvement in the response to chronic heat stress [1].
• Loss of function of the Schizosaccharomyces pombe gap1 gene results in the same phenotypes as those caused by an activated ras1 mutation, i.e., hypersensitivity to the mating factor and inability to perform efficient mating [2].
• The ras1 mutant strain was also avirulent in an animal model of cryptococcal meningitis [3].
• Overexpression of ras1+, an essential gene for sexual development, did not rescue the sterility of rapamycin-treated cells [4].

High impact information on RAS1

• We showed previously that Yin6 cooperates with Ras1 to mediate chromosome segregation; here, we demonstrate that Ras1 similarly regulates the proteasome via Rpn5 [5].
• The lethality resulting from disruption of the CDC25 gene can be suppressed by the presence of the activated RAS2val19 gene, but not by high copy plasmids expressing a normal RAS2 or RAS1 gene [6].
• In contrast to the S. cerevisiae RAS1 and RAS2 gene products, the YPT protein seems to be involved, directly or indirectly, in microtubule organization and function [7].
• We have analyzed the function of the only ras homolog in S. pombe detectable by Southern blotting, ras1, which is homologous to mammalian ras genes and has been cloned [8].
• The cell body of a ras1- strain is extensively deformed, and a ras1-/ras1- diploid sporulates very poorly [8].

Biological context of RAS1

• We present a genetic analysis of RAS1 and RAS2 of S. cerevisiae, two genes that are highly homologous to mammalian ras genes [9].
• By constructing in vitro ras genes disrupted by selectable genes and introducing these by gene replacement into the respective ras loci, we have determined that neither RAS1 nor RAS2 are by themselves essential genes [9].
• The yeast RAS1 and RAS2 genes appear to be involved in control of cell growth in response to nutrients [10].
• TS1 cells accumulate as unbudded cells upon temperature shift from 30 to 37 degrees C, thus showing that the RAS1 and RAS2 gene functions are important for progression through the G1 phase of the cell cycle [11].
• At low levels of expression, a dominant activated phenotype, characterized by low glycogen levels and poor sporulation efficiency, was observed for both full-length RAS1 and RAS2 variants having impaired GTP hydrolytic activity [12].

Anatomical context of RAS1

• Biosynthesis of RAS1 and RAS2 proteins of Saccharomyces cerevisiae involves processing, fatty acid acylation and transport to plasma membranes [13].
• We demonstrate the pathway for the biosynthesis of RAS1 and RAS2 gene products of Saccharomyces cerevisiae leading to their localization in membranes [14].
• In fission yeast, Scd1/Ral1 is a putative guanine nucleotide exchange factor for Cdc42sp and also acts as a Ras1 effector necessary for the regulation of cytoskeleton organization [15].

Associations of RAS1 with chemical compounds

• Activating mutations (valine 19 or leucine 68) were introduced into the Saccharomyces cerevisiae RAS1 and RAS2 genes [12].
• This enzyme activity, detected by using a synthetic peptide sequence based on the C-terminus of a ras protein, may be responsible not only for the essential methylation of the farnesyl cysteine residue of a mating factor, but also for the methylation of yeast RAS1 and RAS2 proteins and possibly other polypeptides with similar C-terminal structures [16].
• Saccharomyces cerevisiae expresses two RAS gene products (RAS1 and RAS2) highly homologous to mammalian p21ras which mediate glucose-stimulated cyclic-AMP formation [17].
• A ras1 strain transformed with this plasmid was subjected to ethyl methanesulfonate mutagenesis and nystatin enrichment [18].
• However, even when the adenosine 3',5'-monophosphate (cAMP) pathway was bypassed, the double disruption of RAS1 and RAS2 resulted in defects in growth at both low and high temperatures [19].

Physical interactions of RAS1

• Yeast two-hybrid assays suggested that Ras1 interacts only with the RA but not any other identifiable domains of Cdc35 [20].

Regulatory relationships of RAS1

• A mutant allele of RAS1 that dominantly interferes with the wild-type Ras function in the yeast Saccharomyces cerevisiae was discovered during screening of mutants that suppress an ira2 disruption mutation [21].
• Candida albicans Ras1 is speculated to similarly activate Cdc35, the orthologue of Cyr1, for hyphal development [20].
• Ras1-induced hyphal development in Candida albicans requires the formin Bni1 [22].
• When ammonium is absent or present at low concentrations, Mep2p activates both the Cph1p-dependent mitogen-activated protein (MAP) kinase pathway and the cAMP-dependent signalling pathway in a Ras1p-dependent fashion via its C-terminal cytoplasmic tail, which is essential for signalling but dispensable for ammonium transport [23].

Other interactions of RAS1

• Differential activation of yeast adenylyl cyclase by Ras1 and Ras2 depends on the conserved N terminus [24].
• We also show that a-factor, RAS1 and RAS2 are physiological methyl-accepting substrates for this enzyme by demonstrating that these proteins are not methylated in a ste14 null mutant [25].
• Genetic analysis suggests that S. pombe Gap1 functions primarily as a negative regulator of Ras1, like S. cerevisiae GAP homologs encoded by IRA1 and IRA2, but is unlikely to be a downstream effector of the Ras protein, a role proposed for mammalian GAP [2].
• Epistatic interactions indicate that the ste6 gene functions upstream of ras1 [26].
• Glucose-induced 32P incorporation into inositolphospholipids and formation of [3H]inositol phosphates were more pronounced in RAS-related mutants such as ras1, ras1 ras2 bcy1, and RAS2Val19 than in the wild-type strain [27].

Analytical, diagnostic and therapeutic context of RAS1

• The replicative life span of Saccharomyces cerevisiae was previously shown to be modulated by the homologous signal transducers Ras1p and Ras2p in a reciprocal manner [28].
• Mst50 also interacts with Ras1, Ras2, Cdc42, and Mgb1 in yeast two-hybrid assays [29].
• The Ras1-RA interaction was further confirmed by in vitro binding assays of purified RA domain and Ras1 and by co-immunoprecipitation of Ras1 and Cdc35 from cell lysates [20].
• To analyze the importance of functional domains of the Byr2 kinase, a biological assay was used that exploited the ability of Byr2 to partially bypass the need for Ras1 in sporulation [30].
• Cell fractionation and immunofluorescence showed that Ras1 was localized to the plasma membrane and that Byr2 was in the cytoplasm [31].

References