Cyclic AMP-dependent protein kinase phosphorylates and inactivates the yeast transcriptional activator ADR1

Cherry, Joel R.; Johnson, Torrey R.; Dollard, Catherine; Shuster, Jeffrey R.; Denis, Clyde L.

doi:10.1016/0092-8674(89)90244-4

Cited by 237 publications

(177 citation statements)

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“…Adrl is not a regulator of the heat shock genes. So far only one yeast transcription factor, Adrl, was shown to be regulated by cPKA (13). Adrl is an activator of the glucose-repressed ADH2 gene, and its activity is suppressed in the bcyl strain (13, 16).…”

Section: Resultsmentioning

confidence: 99%

The yeast and mammalian Ras pathways control transcription of heat shock genes independently of heat shock transcription factor.

Engelberg¹,

Zandi²,

Parker³

et al. 1994

Mol. Cell. Biol.

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Yeast strains in which the Ras-cyclic AMP (cAMP) pathway is constitutively active are sensitive to heat shock, whereas mutants in which the activity of this pathway is low are hyperresistant to heat shock. To determine the molecular basis for these differences, we examined the transcriptional induction of heat shock genes in various yeast strains. Activation of heat shock genes was attenuated in the strains in which the Ras-cAMP pathway is constitutively active. In contrast, in a strain deficient in cAMP production, several heat shock genes were induced by removal of cAMP from the medium. These results indicate that the Ras-cAMP pathway affects the induction of heat shock genes. In all of the mutants, heat shock transcription factor expression and activity were identical to those in wild-type cells. The response to heat shock in Ha-rastransformed rat fibroblasts was also studied. While no induction of Hsp68 was observed in Ha-ras-transformed cells, proper regulation of heat shock transcription factor was found. Therefore, in mammals, as in Saccharomyces cerevisiae, the Ras pathway controls the transcription of heat shock genes via a mechanism not involving the heat shock transcription factor.The ras proto-oncogenes are highly conserved from yeasts to humans (reviewed in reference 12). These genes encode small membrane-associated GTP binding proteins that transduce signals generated at the cell surface to intracellular effectors (3,7,24,59). The mammalian Ha-Ras protein seems to interact with the serine or threonine kinase [77][78][79]85) and somehow leads to its activation. This results in activation of a protein kinase cascade (18,73,83) that induces gene expression through phosphorylation of transcription factors (reviewed in reference 25). One transcription factor affected by Ha-Ras is c-Jun (6), and another is NF-KB (17). In addition to positive modulation of the transcription factors' activity, HaRas may also negatively regulate certain transcription factors.In the yeast Saccharomyces cerevisiae, It was shown that expression of heat shock proteins (hsps) under nonshock conditions confers hyperresistance to heat shock (27,42,56). Therefore, it seems reasonable that resistance and sensitivity to heat shock are mediated at the level of hsp gene transcription. Indeed, it was shown that cyri cells express three proteins with a molecular mass of 72 kDa (65). These proteins, which were probably hsps, were not induced in the bcyl strain (65). Other studies showed that one of the heat shock genes, SSA3, was activated in the cyril strain in the absence of heat shock (9, 80). Also, the UBI4 gene, coding for polyubiquitin, was found to be regulated both by heat shock and cAMP (72). It is still not known, however, whether the Ras-cAMP pathway is a general regulator of hsp gene expression. It is also not known whether mammalian Ha-Ras activation also affects hsp gene expression. Furthermore, both in yeasts and in mammals, the relationship between the Ras pathway and the heat shock transcription factor (HSF [described bel...

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Section: Resultsmentioning

confidence: 99%

The yeast and mammalian Ras pathways control transcription of heat shock genes independently of heat shock transcription factor.

Engelberg¹,

Zandi²,

Parker³

et al. 1994

Mol. Cell. Biol.

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“…We finally asked whether at least one among five aldehyde dehydrogenase genes (ALD2, ALD3, ALD4\ Cherry et al (1989), Dombek et al (1993Dombek et al ( , 1999, Yang et al (1994), Kratzer & Schu $ ller (1997) and Dombek & Young (1997).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its DNA-binding domain, Adr1 also contains four transcription activation domains (TADI-IV) which contact several coactivators and basal transcription factors such as Ada2, Gcn5 and TFIIB as well as subunits of TFIID (Cook et al, 1994 ;Chiang et al, 1996 ;Komarnitsky et al, 1998). Although several regulators of UAS1\Adr1-dependent gene expression have been described [the Cat1\Snf1\ Ccr1 protein kinase (Ciriacy, 1977 ;Denis, 1987), cAMP-dependent protein kinases Tpk1, 2, 3 (Cherry et al, 1989) and the protein phosphatase complex The synthetic DNA fragment ADH2-UAS2 was inserted into the promoter test plasmid pJS401 (∆UAS-ICL1-lacZ URA3 2µ), which contains the basal ICL1 promoter but is devoid of all upstream regulatory elements. Orientation and copy number of ADH2-UAS2 with respect to the TATA box (black square) is indicated by arrows.…”

Section: Introductionmentioning

confidence: 99%

Adr1 and Cat8 synergistically activate the glucose-regulated alcohol dehydrogenase gene ADH2 of the yeast Saccharomyces cerevisiae

Walther¹,

Schüller²

2001

Microbiology

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Glucose-repressible alcohol dehydrogenase II, encoded by the ADH2 gene of the yeast Saccharomyces cerevisiae, is transcriptionally controlled by the activator Adr1, binding UAS1 of the control region. However, even in an adr1 null mutant, a substantial level of gene derepression can be detected, arguing for the existence of a further mechanism of activation. Here it is shown that the previously identified UAS2 contains a distantly related variant of the carbon source-responsive element (CSRE) initially found upstream of gluconeogenic genes. In a mutant defective for the CSRE-binding factor Cat8, derepression of an ADH2-lacZ fusion was reduced to about 12 % of the wildtype level. Gene expression in a cat8 adr1 double mutant decreased almost to the basal level of the glucose-repressed promoter. CSRE ADH2 present in a single copy turned out to be a weak UAS element, while a significant synergism of gene activation was found in the presence of at least two copies. Its importance for regulated gene activation was confirmed by site-directed mutagenesis of the CSRE in the natural ADH2 control region. Direct binding of Cat8 to CSRE ADH2 could be shown by electrophoretic retardation of the corresponding protein/DNA complex in the presence of a specific antibody. In contrast to what was shown previously for CSRE sequence variants, no significant influence of the isofunctional activator Sip4 on CSRE ADH2 was detected. In conclusion, these results show a derepression of ADH2 by synergistically acting regulators Adr1 (interacting with UAS1) and Cat8, binding to UAS2 (l CSRE ADH2 ).

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“…Activated PKA shifts the metabolic flux away from gluconeogenesis and toward glycolysis by regulating key enzymes in these processes including fructose-1,6-bisphosphatase and phosphofructokinase-2 (3). Phosphorylation by PKA inactivates the transcription factor Adr1, a positive regulatory factor for the transcription of the respiratory enzyme Adh2 (4). In addition, PKA promotes the breakdown of glycogen and trehalose by inhibiting enzymes involved in synthesis (trehalose synthase and glycogen synthase) and activating enzymes involved in breakdown (trehalase and glycogen phosphorylase) of these storage carbohydrates.…”

mentioning

confidence: 99%

The yeast A kinases differentially regulate iron uptake and respiratory function

Robertson

Causton

Young

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

165

150

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Tpk2, but not Tpk1 or Tpk3, is required for pseudohyphal growth. Genome-wide transcriptional profiling has revealed unique signatures for each of the three A kinases leading to the identification of additional functional diversity among these proteins. Tpk2 negatively regulates genes involved in iron uptake and positively regulates genes involved in trehalose degradation and water homeostasis. Tpk1 is required for the derepression of branched chain amino acid biosynthesis genes that seem to have a second role in the maintenance of iron levels and DNA stability within mitochondria. The fact that TPK2 mutants grow better than wild types on nonfermentable carbon sources and on media deficient in iron supports the unique role of Tpk2 in respiratory growth and carbon source use.I n yeast, cAMP acting through the A kinases (PKA) provides a key regulatory signal for growth on diverse carbon sources. Growth on fermentable carbon sources (e.g., glucose, fructose, and sucrose) requires a higher basal level of cAMP than does growth on nonfermentable carbon sources (e.g., ethanol, glycerol, and acetate). Therefore, the level of cAMP must decrease in order for cells to switch from growth on fermentable carbon sources to growth on nonfermentable carbon sources (the diauxic shift; ref. 1). Addition of glucose to yeast cells growing on a nonfermentable carbon source or starved for glucose results in a transient peak in intracellular cAMP levels. This transition to fermentation requires both the transient increase of cAMP and the cAMP-dependent PKA (2). Activated PKA shifts the metabolic flux away from gluconeogenesis and toward glycolysis by regulating key enzymes in these processes including fructose-1,6-bisphosphatase and phosphofructokinase-2 (3). Phosphorylation by PKA inactivates the transcription factor Adr1, a positive regulatory factor for the transcription of the respiratory enzyme Adh2 (4). In addition, PKA promotes the breakdown of glycogen and trehalose by inhibiting enzymes involved in synthesis (trehalose synthase and glycogen synthase) and activating enzymes involved in breakdown (trehalase and glycogen phosphorylase) of these storage carbohydrates.The transcriptional changes occurring in the transition from fermentative growth to respiratory growth have been monitored by genome expression arrays (5). As glucose is depleted, transcription of genes involved in respiration, the tricarboxylic acid cycle, the glyoxylate cycle, gluconeogenesis, and storage carbohydrate synthesis is induced, whereas transcription of genes involved in glycolysis and protein synthesis is repressed (5). Consistent with the shift to respiratory growth, cytoplasmic ribosomal protein genes are repressed, and mitochondrial ribosomal genes are induced. In view of the role of cAMP and the PKAs in the use of carbon sources, these results raise the question of whether the PKAs function in respiratory growth and whether they are redundant for this function.To elucidate more broadly the functional differences between the PKA catalytic subunits, we ...

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Cyclic AMP-dependent protein kinase phosphorylates and inactivates the yeast transcriptional activator ADR1

Cited by 237 publications

References 44 publications

The yeast and mammalian Ras pathways control transcription of heat shock genes independently of heat shock transcription factor.

The yeast and mammalian Ras pathways control transcription of heat shock genes independently of heat shock transcription factor.

Adr1 and Cat8 synergistically activate the glucose-regulated alcohol dehydrogenase gene ADH2 of the yeast Saccharomyces cerevisiae

The yeast A kinases differentially regulate iron uptake and respiratory function

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