Disease relevance of SKO1

• SKO1/ACR1, which encodes a CREB-like repressor protein in yeast, was isolated as a high copy suppressor of the toxicity caused by RAP1 overexpression [1].
• Disruption of the ACR1 gene conduces to an arsenite and arsenate hypersensitivity phenotype [2].

High impact information on SKO1

• During hyperosmotic stress, Hog1 MAP kinase associates with target promoters, phosphorylates Sko1, and converts Sko1 into a transcriptional activator [3].
• Here we demonstrate that the ion homeostasis determinant, HAL1, is regulated by two antagonistically operating bZIP transcription factors, the Sko1p repressor and the Gcn4p activator [4].
• The Sko1p repressor and Gcn4p activator antagonistically modulate stress-regulated transcription in Saccharomyces cerevisiae [4].
• In addition, Acr1 does not affect a number of phenotypes that arise from loss of Aca2 [5].
• A glutathione S-transferase-Sko1 fusion protein binds specifically to the URSCRE-ENA1 element [6].

Biological context of SKO1

• All five Sko1p target genes are induced by oxidative stress, and induction involves Yap1p [7].
• The ATF/CREB consensus sequence is not statistically overrepresented in confirmed Sko1 target promoters, although some sites are evolutionarily conserved among related yeast species, suggesting that they are functionally important in vivo [8].
• Taken together our results suggest that Sko1 operates a transcriptional network upon osmotic stress, which involves other specific transcription factors and a phosphatase that regulates the key component of the signal transduction pathway [8].
• The central part (315) of Sko1p, containing the PKA phosphorylation sites and the basic domain-leucine zipper domain, is essential for its nuclear localization [9].
• We analyzed the function of the SACE of the left arm of chromosome VIII in vivo and found its ATF/CREB site to act as UAS/URS of the COS8 promoter, effected by the yeast bZip proteins Sko1p, Aca1p, and Aca2p [10].

Anatomical context of SKO1

• Sko1p is localized in the nucleus of unstressed cells, and it redistributes to the cytosol upon severe salt stress (1 m NaCl) [9].
• Interestingly, Sko1p, a downstream regulator of the high osmolarity pathway is known to bind to the AFT/CRE binding site, suggesting a possible role for the Hog1 pathway in the response to cell wall stress [11].

Associations of SKO1 with chemical compounds

• Within the bZIP domain, ACR1 most strongly resembles the mammalian cyclic AMP-responsive transcriptional regulators CREB and CREM; it is less similar to GCN4 and YAP1, two previously described yeast bZIP transcriptional activators that recognize the related AP-1 sequence (consensus TGACTCA) [12].
• The cluster of three genes, ACR1, ACR2, and ACR3, previously was shown to confer arsenical resistance in Saccharomyces cerevisiae [13].
• In contrast, acr1, acr3, and acr4 mutants were resistant to papulacandin B (an antibiotic containing a disaccharide linked to two fatty acid chains that also inhibits beta-glucan synthesis), but acr2 mutants were susceptible to this antibiotic [14].

Physical interactions of SKO1

• We found that SKO1 also binds to a CRE-like site in SUC2, a yeast gene encoding invertase which is under positive control by cAMP [15].

Enzymatic interactions of SKO1

• Hog1 phosphorylates Sko1 in vitro at multiple sites within the N-terminal region [16].

Other interactions of SKO1

• Repressors and upstream repressing sequences of the stress-regulated ENA1 gene in Saccharomyces cerevisiae: bZIP protein Sko1p confers HOG-dependent osmotic regulation [6].
• Studies with the yeast transcription factors GCN4, SKO1 and YAP1, which bind CRE-like sequences, showed no influence on expression of the 35S promoter indicating that a yet unknown factor is involved in activation [17].
• Acr1 does not fully account for osmotic regulation through ATF/CREB sites, and a novel Hog1-dependent activator(s) that is not a bZIP protein is required for ATF/CREB site activation in response to high salt [5].
• Sko1p repressor activity is associated to its binding to the Ssn6p x Tup1p complex [9].
• Salt-induced export of Sko1p from the nucleus is independent of Hog1p and of the Bcy1p regulatory subunit of PKA [9].
• The results thus provide evidence that Plc1p and inositol polyphosphates affect derepression of Sko1p-Ssn6p-Tup1p-controlled genes by a mechanism that involves recruitment of the SAGA complex and TATA-binding protein [18].

Analytical, diagnostic and therapeutic context of SKO1

• By combining chromatin immunoprecipitation and microarrays containing essentially all intergenic regions, we estimate that yeast cells contain approximately 40 Sko1 target promoters in vivo; 20 Sko1 target promoters were validated by direct analysis of individual loci [8].

References