Disease relevance of CYR1

• Mixing a crude extract from the E. coli transformant carrying CYR1 with a crude extract from cells carrying RAS2 reconstituted the GTP-dependent adenylate cyclase [1].
• Long-term increases in neurotransmitter release from neuronal cells expressing a constitutively active adenylate cyclase from a herpes simplex virus type 1 vector [2].
• The crystal structure of the class IV adenylyl cyclase (AC) from Yersinia pestis (Yp) is reported at 1.9 A resolution [3].
• To separate the signaling and desensitization of beta2AR, which mediates stimulation of adenylyl cyclase, S49 lymphoma cys- cells that lack the alpha subunit of Gs were used [4].
• Dermal fibroblasts had higher AC activity and intracellular cAMP levels than the colon cancer lines (p less than 0.05) [5].

High impact information on CYR1

• Adenylyl cyclase activity in membranes from cells that lacked CAP was not stimulated by RAS2 proteins in vitro [6].
• These results demonstrate that SRV2 protein is required for RAS-activated adenylate cyclase activity, but that it participates in other essential cellular functions as well [7].
• Adenylyl cyclase from S. cerevisiae contains at least two subunits, a 200 kd catalytic subunit and a subunit with an apparent molecular size of 70 kd, which we now call CAP (cyclase-associated protein) [6].
• Mutants lacking CAP had four additional phenotypes that appear to be unrelated to effects of the RAS/adenylyl cyclase pathway: the inability to grow on rich medium (YPD), temperature sensitivity on minimal medium, sensitivity to nitrogen starvation, and a swollen cell morphology [6].
• Estrogen was found to lead to higher steady-state levels of adenylate cyclase mRNA but not to affect the expression of the RAS1 and RAS2 genes, although these can also alter the intracellular cAMP level [8].

Chemical compound and disease context of CYR1

• Adenylate cyclase activity and cyclic adenosine monophosphate levels in colon cancer lines and dermal fibroblasts and the effects of cholera toxin and epidermal growth factor [5].
• In reconstitution experiments, rat GS-alpha(S and L), solubilized from yeast membranes with 1% cholate, conferred NaF-, (-)isoproterenol-, and guanine nucleotide-dependent sensitivity to adenylyl cyclase catalytic units in S49 lymphoma cyc- cell membranes, which are devoid of endogenous GS-alpha [9].

Biological context of CYR1

• Various truncated CYR1 genes of Saccharomyces cerevisiae were fused to efficient promoters and expressed in Escherichia coli and S. cerevisiae cells with or without the RAS genes [10].
• The catalytic domain of adenylate cyclase encoded by the 3'-terminal 1.3 kb region of the open reading frame of the CYR1 gene produced cyclic AMP, irrespective of the presence of RAS genes [10].
• Estrogen can regulate the cell cycle in the early G1 phase of yeast by increasing the amount of adenylate cyclase mRNA [8].
• Results showed that estrogen stimulated the recovery of growth from G0 arrest induced by nutrient limitation or ts mutation of cdc35 (adenylate cyclase) in the early G1 phase, and inhibited entry into the resting G0 phase by increasing the intracellular cAMP level [8].
• Entry into meiosis in Saccharomyces cerevisiae cells is regulated by starvation through the adenylate cyclase/cAMP-dependent protein kinase (AC/PK) pathway [11].

Anatomical context of CYR1

• Here we show that mutations in CYR1 and SCH9 also extend the replicative life span of individual yeast mother cells [12].
• The relative amount of membrane-bound adenylate cyclase was drastically reduced in cdc25 ts membranes when subjected to the restrictive temperature, while no significant change was observed in the wild type [13].
• These data suggest that Cdc25 might not be required in certain conditions for the guanine nucleotide exchange reaction in Ras and that it might be implicated in anchoring the Ras/adenylate cyclase system to the plasma membrane [13].
• In this investigation, we have studied whether the posttranslational processing of Ki- and Ha-ras p21s is critical for their stimulation of yeast adenylate cyclase in a cell-free system [14].
• The data suggest an interaction of CAP with adenylyl cyclase in Dictyostelium and an influence on signaling pathways directly as well as through its function as a regulatory component of the cytoskeleton [15].

Associations of CYR1 with chemical compounds

• Screening of approximately 13,000 mutagenized colonies for galactose-dependent growth at a high temperature (37 degrees) yielded six temperature-sensitive ras2 (ras2ts) mutations and one temperature-sensitive cyr1 (cyr1ts) mutation that can be suppressed by overexpression or increased dosage of RAS2 [16].
• It is also shown that 6-deoxyglucose can activate adenylate cyclase in the absence of CDC25 gene product [13].
• The mutation predicts the replacement of threonine by isoleucine at position 1651 of yeast adenylate cyclase [17].
• Incubation of wild-type membranes with lysophosphatidylinositol, lysophosphatidylserine, or lysophosphatidylcholine stimulated adenylyl cyclase activity in the absence and presence of RAS between 2-10-fold depending upon the individual lipid [18].
• An inhibitor of mammalian adenylate cyclase, MDL-12330A, was tested in combination with azoles; a synergistic effect was observed against azole-susceptible and -resistant strains of C. albicans and five of six non-C. albicans Candida species [19].

Physical interactions of CYR1

• Yeast two-hybrid assays suggested that Ras1 interacts only with the RA but not any other identifiable domains of Cdc35 [20].
• Like the wild-type enzyme, the RAS-dependent activity of the mutant adenylate cyclase is turned on by the GTP-bound form of the RAS2 protein [17].
• The SH3 domain of the S. cerevisiae Cdc25p binds adenylyl cyclase and facilitates Ras regulation of cAMP signalling [21].
• Sgt1p contributes to cyclic AMP pathway activity and physically interacts with the adenylyl cyclase Cyr1p/Cdc35p in budding yeast [22].

Enzymatic interactions of CYR1

• The results indicate that either rapamycin did not suppress the derepression of sexual development of strains in which adenylate cyclase was deleted or the cyclic AMP-dependent protein kinase encoded by pka1 was mutated [23].

Regulatory relationships of CYR1

• The adenylate cyclase/protein kinase cascade regulates entry into meiosis in Saccharomyces cerevisiae through the gene IME1 [11].
• Anti-Cdc25 antibodies inhibit guanyl nucleotide-dependent adenylyl cyclase of Saccharomyces cerevisiae and cross-react with a 150-kilodalton mammalian protein [24].
• Interactions between adenylate cyclase and the yeast GTPase-activating protein IRA1 [25].
• Candida albicans Ras1 is speculated to similarly activate Cdc35, the orthologue of Cyr1, for hyphal development [20].
• Yeast strains carrying the IAC mutation have elevated levels of adenylate cyclase activity. bcy1 is a mutation that suppresses the lethality in adenylate cyclase deficient yeast [26].

Other interactions of CYR1

• The E. coli transformant carrying the yeast RAS2 or RAS2val19 gene had no adenylate cyclase activity [1].
• In the yeast Saccharomyces cerevisiae, the activation of adenylate cyclase requires the products of the RAS genes and of CDC25 [27].
• We have concluded that IRA1 is a strong candidate for a protein involved in anchoring adenylate cyclase to the membrane [25].
• The activity of adenylate cyclase in the yeast Saccharomyces cerevisiae is controlled by two G-protein systems, the Ras proteins and the Galpha protein Gpa2 [28].
• Some sra1 and SRA4 and all SRA3 mutations were RAS independent, allowing growth of yeast cells that lack a functional RAS gene [29].

Analytical, diagnostic and therapeutic context of CYR1

• 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].
• Southern blotting using a 5'-proximal probe of the Saccharomyces cerevisiae CYR1 gene has revealed heterogeneity in laboratory strains [30].
• This in vitro system allowed a quantitative evaluation of the effects of positive and negative effectors of RAS on adenylyl cyclase and the biochemical analysis of conditions inducing a phenotype of permanently activated adenylyl cyclase [31].
• Molecular cloning of the tsm0185 gene responsible for adenylate cyclase activity in Saccharomyces cerevisiae [32].
• A monoclonal antibody previously raised against the peptide was used to purify adenylyl cyclase by affinity chromatography [33].

References