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Query: UNIPROT:P06889 (Mol)
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To investigate the role of the trans-acting transcription factor encoded by the essential SPT14 (SPT = Suppressor of Ty insertion mutations) gene, we have cloned, mapped and sequenced the gene. From the analysis of the effect of spt14 mutations on expression of various genes, we conclude that the SPT14 product has an important role in activation of Ty transcription as well as in the regulation of other genes including HIS4 and several of the a- and alpha-specific mating type genes. Similarities in the phenotypes of spt14 and spt13 mutants (suppression of Ty insertion mutations but not delta insertion mutations), lead to the suggestion that the SPT14 gene and the previously characterized SPT13/GAL11 gene might encode transcriptional regulators with related functions. Our current findings show that in contrast to SPT13/GAL11, which appears negatively to regulate Ty transcription, SPT14 plays a role in the activation of Ty transcription. Thus, despite the similarities in the suppression phenotype exhibited by spt13 and spt14 mutants, SPT13/GAL11 and SPT14 probably differ in their transcriptional roles.
Mol Gen Genet 1991 Nov
PMID:The Saccharomyces cerevisiae SPT14 gene is essential for normal expression of the yeast transposon, Ty, as well as for expression of the HIS4 gene and several genes in the mating pathway. 166 May 67

The his4-912 delta mutation is an insertion of the long terminal repeat (delta) of the yeast retrotransposon Ty into the HIS4 promoter region, such that the delta is 97 base pairs upstream of the HIS4 transcription initiation site. Strains carrying the his4-912 delta allele are His- at 23 degrees C; this phenotype can be reversed either by growth at 37 degrees C or by mutations in trans-acting SPT genes. Under conditions in which his4-912 delta confers a His- phenotype. HIS4 transcription initiates at the delta initiation site, rather than at the HIS4 initiation site, producing a longer, nonfunctional transcript. Under conditions in which the strain is His+, transcription initiates at the wild-type HIS4 initiation site. To understand how transcription is balanced between the delta and HIS4 promoters, we have selected for cis-acting suppressors of his4-912 delta. Two classes defined by six independent mutations restore synthesis of a functional HIS4 transcript. The first class is an A-to-G base change 1 base upstream of the proposed delta TATA sequence. These mutants do not synthesize the delta-initiated transcript; instead, they synthesize only the wild-type HIS4 transcript. The second class of mutations alters base pairs surrounding the functional HIS4 TATA sequence. The two strongest His+ mutants of this class synthesize the wild-type HIS4 transcript at levels consistent with their His+ phenotype. Surprisingly, these two mutants also have a reduced level of the delta-initiated transcript relative to the his4-912 delta parent. Analysis of these mutants indicates that the level of transcription from one promoter can affect the level of transcription from the other promoter and suggests that delta and HIS4 transcription signals compete for initiation of transcription from each site.
Mol Cell Biol 1988 Nov
PMID:Genetic evidence for promoter competition in Saccharomyces cerevisiae. 285 Apr 65

Insertion of two different Ty elements into the Saccharomyces cerevisiae HIS4 regulatory region eliminates transcription of HIS4. Transcription can be restored by genetic rearrangements involving the Ty element inserted at HIS4. Several deletions, an inversion, a translocation, and a gene conversion are capable of restoring HIS4 transcription. Some of the rearrangements result in new transcriptional initiation sites. One type of revertant of his4-912 results from recombination between the delta elements flanking the Ty element, leaving a solo delta in place of the complete Ty. Strains carrying a Ty912 delta at HIS4 are His- at 23 degrees C. Unlinked suppressors (SPT) lead to suppression of this His- phenotype and increase levels of the normal HIS4 transcript. These suppressor genes affect not only the amount of transcription from the normal HIS4 initiation site, but also that from new initiation sites within Ty sequences adjacent to HIS4.
Mol Cell Biol 1984 Jul
PMID:Effects of Ty insertions on HIS4 transcription in Saccharomyces cerevisiae. 609 55

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
J Mol Cell Cardiol 1995 Mar
PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

Although there is good evidence that adenosine contributes to the ability of ischaemic preconditioning to reduce myocardial ischaemic damage (infarct size) there is no evidence that it contributes to the marked antiarrhythmic effects of this endogenous protective mechanism. We have examined this in anaesthetized open-chest mongrel dogs by administering the non-selective adenosine receptor blocking drug 8-sulfophenyltheophylline (8-SPT) (1 mg/kg) given by intracoronary administration 10 min before both 5 min preconditioning coronary artery occlusions and also before the prolonged 25 min LAD occlusion i.e. in a total dose of 3 mg/kg. The only haemodynamic effect of 8-SPT was a reduction in coronary (LAD) blood flow and an increase in cardiovascular resistance. It was difficult to precondition dogs in the presence of 8-SPT; the number of ventricular premature beats was significantly higher (61 +/- 6 v 8 +/- 4; P < 0.01) during the initial preconditioning occlusion and the incidence of ventricular fibrillation during the preconditioning procedure was higher in the presence of the drug (5/11 v 4/20; P < 0.05). Nevertheless, it was still possible to precondition these dogs in the presence of the drug. No VF occurred during the prolonged occlusion (cf. 50% in the controls) and the number of episodes of ventricular tachycardia, and the number of ventricular premature beats in dogs preconditioned in the presence of 8-SPT was similar to those in dogs preconditioned without 8-SPT and significantly (P < 0.01 or P < 0.05) less than in control, non-preconditioned dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1995 Jan
PMID:Pronounced antiarrhythmic effects of preconditioning in anaesthetized dogs: is adenosine involved? 776 Mar 56

We used three interventions to test critically the theory that ischemic preconditioning is the result of translocation of cytosolic protein kinase C (PKC) into the membranes where it can be activated. If that theory were true then kinase activity should not be necessary during the preconditioning ischemia and thus blocking kinase activity at this time should not block protection. Secondly, since most translocation processes in the cell are accomplished by cytoskeletal microtubules, disrupting them with colchicine should also block protection from preconditioning. Finally, translocating PKC by transient exposure to PMA, should still require adenosine receptor activation to reactivate the PKC pathway during the subsequent ischemia. Blocking kinase activity with staurosporine during a 30 min insult completely blocks protection in preconditioned hearts but when staurosporine treatment was confined to the preconditioning episode protection was not blocked in five of the eight hearts studied. Microtubule disruption with colchincine did block the protective effect of preconditioning (38.3 +/- 1.9% infarction v 40.6 +/- 4.1% in non-preconditioned). Colchicine had no effect on infarct size in the non-preconditioned group. Five min PMA treatment plus 10 min washout significantly limited infarct size in isolated rabbit hearts subjected to 30 min regional ischemia (5.9 +/- 1.1% v 31 +/- 3.5% infarction in control). PMA's protection was blocked by adding the adenosine receptor blocker, SPT, during the sustained ischemia (38.1 +/- 6.1% infarction). All three of these experiments strongly support the translocation theory of ischemic preconditioning.
J Mol Cell Cardiol 1994 May
PMID:Evidence that translocation of protein kinase C is a key event during ischemic preconditioning of rabbit myocardium. 807 20

The aim of this study was: (1) to elucidate in more detail the relationship between stress protein expression and brief periods of ischaemia and reperfusion, such as occur during early (classical) ischaemic preconditioning (PC) in the rabbit myocardium; (2) to determine whether stress protein expression is affected by adenosine receptor modulation, since adenosine is a mediator of the preconditioning response. We have studied the expression of the 60 kDa (hsp60); 70 kDa (hsp70-inducible and constitutive isoforms) and 27 kDa (hsp27) stress proteins and the mitochondrial ATP-synthase beta-subunit using Northern blotting. Hsp60, hsp70 and hsp27 expression were also determined at the protein level by Western blotting. Total RNA and proteins were prepared from frozen samples of ischaemic left ventricle and non-ischaemic right ventricle rabbit myocardium after the following treatments (1) sham-operated; (2) 15 min stabilization + 5 min coronary occlusion + 10 min reperfusion (PC); (3) PC + 30 min coronary occlusion (I); (4) PC + 30 min coronary occlusion + 2 h reperfusion (I/R) (5) the adenosine receptor antagonist 8-(p-sulpho-phenyl) theophyline (SPT) given 5 min prior to PC; (6) the adenosine receptor agonist 2-chlorocyclopentyl-N6-adenosine (CCPA) given in place of PC. A transient, approximately two-fold elevation in hsp60 mRNA occurred following 5 min coronary occlusion + 10 min reperfusion (PC) which was stable during a subsequent 30 min ischaemia (I), but returned to baseline during the second (2 h) reperfusion (I/R). An inducible hsp70 mRNA species appeared within 10 min of the second (30 min) coronary occlusion (I) which continued to increase to high levels during the second (2 h) reperfusion (I/R). Hsp27 mRNA expression was not altered following PC or subsequent ischaemia and reperfusion (I/R). ATP synthase beta-subunit mRNA did not change during PC or I but decreased during the subsequent 2 h reperfusion (I/R). Western blot analysis showed no change in left ventricle ischaemic zone hsp60, hsp70i/hsc70 or hsp27 protein during PC compared to an approximately two-fold elevation of hsp70i 24 h following whole body heat stress or 24 h following 4 x 5 min coronary occlusion (as reported by Marber et al., 1993). However, hsp70i, hsp60 and hsp27 showed significant decreases in immunodetectable protein following subsequent ischaemia and reperfusion (I/R). SPT inhibited the increase in hsp60 mRNA following PC (P < or = 0.05), but had no effect on hsp70, hsp27 or ATP-synthase mRNA levels. Therefore, differential expression of mRNAs for hsp60 and hsp70 occurred following ischaemia and reperfusion, with hsp70 mRNA expression involving a significant reperfusion-dependent component. CCPA had no effect on expression of mRNAs for hsp60, hsp70, hsp27 or ATP-synthase. We conclude that the early phase of adenosine receptor-dependent preconditioning in the rabbit heart is not mediated via stress protein expression. However, brief ischaemia and reperfusion resulted in differential changes in individual stress protein gene expression which may be due to different physiological and/or biochemical components of ischaemia and reperfusion in the heart. In addition, partial dependence of hsp60 expression on adenosine receptor modulation was observed.
J Mol Cell Cardiol 1995 Oct
PMID:Differential stress protein mRNA expression during early ischaemic preconditioning in the rabbit heart and its relationship to adenosine receptor function. 857 30

The presence of H2A-H2B dimers in nucleosomes can inhibit the binding of transcription factors to chromatin templates. To study the roles of histones H2A and H2B in transcriptional repression in vivo, mutant forms of these histones were analyzed in two different assay systems. Two repression domains were identified in H2A. One domain includes residues that fall in the beginning of the H2A-H2B dimerization region, and the second is in the H2A N terminus, a region of potential interactions with nonhistone proteins. The function of H2A and H2B in one repression assay was found to be dependent on three SPT (suppressor of Ty) genes whose products are important for chromatin-mediated repression. These results suggest that repressive chromatin structure may be established through the interactions of the Spt proteins with these histones. In contrast, other proteins, the products of the HIR (histone regulation) genes, may function to direct H2A and H2B to specific promoters.
Mol Cell Biol 1996 Jun
PMID:Functional analysis of histones H2A and H2B in transcriptional repression in Saccharomyces cerevisiae. 864 61

In this report we described the cloning and characterization of ADA5, a gene identified by resistance to GAL4-VP16-mediated toxicity. ADA5 binds directly to the VP16 activation domain but not to a transcriptionally defective VP16 double point mutant. Double mutants with mutations in ada5 and other genes (ada2 or ada3) isolated by resistance to GAL4-VP16 grow like ada5 single mutants, suggesting that ADA5 is in the same pathway as the other ADA genes. Further, ADA5 cofractionates and coprecipitates with ADA3. However, an ada5 deletion mutant exhibits a broader spectrum of phenotypes than mutants with null mutations in the other ADA genes. Most interestingly, ADA5 is identical to SPT20 (S.M. Roberts and F. Winston, Mol. Cell. Biol. 16: 3206-3213, 1996), showing that it shares phenotypes with the ADA and SPT family of genes. Of the other SPT genes tested, mutants with mutations in SPT7 and, strikingly, SPT15 (encoding the TATA-binding protein) show resistance to GAL4-VP16. We present a speculative pathway of transcriptional activation involving the ADA2-ADA3-GCN5-ADA5 complex and the TATA-binding protein.
Mol Cell Biol 1996 Jun
PMID:ADA5/SPT20 links the ADA and SPT genes, which are involved in yeast transcription. 864 30

The aim of the study was to test if pre-ischemic treatment with bradykinin can protect against infarction in an isolated rat heart model of regional ischemia and reperfusion, and if any such protection is dependent upon activation of protein kinase C (PKC) or mediated through the nitric oxide (NO) pathway. We also investigated if bradykinin B2 receptor activation, alone or in combination with activation of adenosine receptors and alpha-adrenoceptors, are involved in the infarct size reducing effect of ischemic preconditioning. Buffer-perfused rat hearts were subjected to 30 min regional ischemia and 120 min reperfusion. Risk zone was determined by fluorescent particles and infarct size by tetrazolium staining. Treatment with bradykinin (0.5 mumol/l) prior to ischemia significantly reduced infarct size in percentage of risk zone compared to control experiments (infarct size: 9.6 +/- 1.3% v 41.8 +/- 3.6%, P < 0.001). An inhibitor of NO synthesis, NOARG (100 mumol/l), did not interfere with the bradykinin induced protection (infarct size: 13.3 +/- 2.0%), while chelerythrine (2 mumol/l), an inhibitor of protein kinase C, reversed the effect of bradykinin (infarct size: 30.0 +/- 2.8%). NOARG did not influence infarct size in the control group (infarct size: 40.1 +/- 3.2%). Ischemic preconditioning with three cycles of 5 min global ischemia + 5 min reperfusion offered protection similar to bradykinin (infarct size: 8.4 +/- 2.0%). The bradykinin antagonist HOE 140 (1 mumol/l) reversed the effect of bradykinin (infarct size: 42.5 +/- 3.1%), but did not interfere with ischemic preconditioning (infarct size: 7.7 +/- 1.6%). Similarily, combined blockade of alpha-adrenergic, adenosine and bradykinin B2 receptors with p-benzamine (10 mumol/l). SPT (100 mumol/l) and HOE 140 did not interfere with ischemic preconditioning (infarct size: 7.8 +/- 1.1%). Thus, bradykinin can protect against infarction via protein kinase C, but independently of NO. A role for bradykinin in mediating ischemic preconditioning against infarction could not be demonstrated.
J Mol Cell Cardiol 1996 Dec
PMID:Bradykinin protects against infarction but does not mediate ischemic preconditioning in the isolated rat heart. 900 50


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