Journal articles: 'Cre8'

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Cui, Jiangkuan, Huan Peng, Wenkun Huang, Shiming Liu, Duqing Wu, Lingan Kong, Wenting He, and Deliang Peng. "Phenotype and Cellular Response of Wheat Lines Carrying Cre Genes to Heterodera avenae Pathotype Ha91." Plant Disease 101, no. 11 (November 2017): 1885–94. http://dx.doi.org/10.1094/pdis-03-17-0404-re.

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The cereal cyst nematode (CCN, Heterodera avenae), a major limiting factor for wheat production worldwide, is widespread in most wheat-growing regions in China. Accordingly, screening and characterization of resistant (R) wheat sources against H. avenae are very important. In this study, we screened 51 wheat lines, collected from the International Wheat and Maize Improvement Center (CIMMYT), carrying various Cre genes (Cre1, Cre2, Cre3, Cre5, Cre7, Cre8, CreR, and Pt). From that screen, we identified one immune (M) cultivar (with no adult females produced) and five resistant cultivars (with fewer than five females) to H. avenae pathotype Ha91. The Cre3 gene conferred the most effective resistance against H. avenae pathotype Ha91 in both field and greenhouse assays. Conversely, the Cre1 and CreR genes conferred the poorest effective resistance. Using Pluronic F-127 gel and a staining assay, juvenile nematodes invading wheat roots were observed, and nematode development was analyzed. Compared with R and M roots, those of the susceptible (S) wheat cultivar Wenmai19 were more attractive to H. avenae second-stage juveniles (J2s). We observed the retardation of nematode development in R cultivars and tiny white female cysts protruding from the R cultivar VP1620. Nematodes in M roots either disintegrated or remained J2s or third-stage juveniles (J3s) and failed to complete their life cycle. Molting was also suppressed or delayed in R and M genotypes. For both S and R cultivars, syncytia were characterized by cell wall perforations and dense cytoplasm in hypertrophied syncytium component cells. Syncytial size increased gradually with nematode development in S cultivars. Moreover, an incompatibility reaction occurred in M wheat roots: the syncytium was disorganized, exhibiting disintegration and condensed nuclei. These sources of genetic resistance against CCN can potentially be planted in severely infested fields to reduce economic loss or can be used for introgression in breeding.

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Hay, Colin W., Elaine M. Sinclair, Giovanna Bermano, Elaine Durward, Mohammad Tadayyon, and Kevin Docherty. "Glucagon-like peptide-1 stimulates human insulin promoter activity in part through cAMP-responsive elements that lie upstream and downstream of the transcription start site." Journal of Endocrinology 186, no. 2 (August 2005): 353–65. http://dx.doi.org/10.1677/joe.1.06205.

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Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted from the enteroendocrine L-cells of the gut and which acts primarily to potentiate the effects of glucose on insulin secretion from pancreatic β-cells. It also stimulates insulin gene expression, proinsulin biosynthesis and affects the growth and differentiation of the islets of Langerhans. Previous studies on the mechanisms whereby GLP-1 regulates insulin gene transcription have focused on the rat insulin promoter. The aim of this study was to determine whether the human insulin promoter was also responsive to GLP-1, and if so to investigate the possible role of cAMP-responsive elements (CREs) that lie upstream (CRE1 and CRE2) and downstream (CRE3 and CRE4) of the transcription start site. INS-1 pancreatic β-cells were transfected with promoter constructs containing fragments of the insulin gene promoter placed upstream of the firefly luciferase reporter gene. GLP-1 was found to stimulate the human insulin promoter, albeit to a lesser degree than the rat insulin promoter. Mutagenesis of CRE2, CRE3 and CRE4 blocked the stimulatory effect of GLP-1 while mutagenesis of CRE1 had no effect. Analysis of nuclear protein binding to the four CREs showed that, while they share some proteins, each CRE site is unique. Stimulation of transcription by GLP-1 through CRE2, CRE3 and CRE4 resulted in altered protein binding that was different for each of the CRE sites involved. Collectively, these data show that the four human CREs are not simply multiple copies of the rat CRE site and further emphasise that the human insulin promoter is distinct from the rodent promoter.

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Smiley, Richard W., Guiping Yan, and John N. Pinkerton. "Resistance of wheat, barley and oat to Heterodera avenae in the Pacific Northwest, USA." Nematology 13, no. 5 (2011): 539–52. http://dx.doi.org/10.1163/138855410x531862.

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Abstract The cereal cyst nematode, Heterodera avenae, occurs in at least seven western states of the USA and reduces grain yield in localised regions and in selected crop management systems. Virulence phenotypes for H. avenae populations in North America have not been reported. Nine individual assays in six experiments were conducted to determine the reactions of barley, oat and wheat cultivars to five H. avenae populations in the Pacific Northwest (PNW) states of Idaho, Oregon and Washington. Three populations were evaluated for virulence to 23 entries of the 'International Test Assortment for Defining Cereal Cyst Nematode Pathotypes', plus selected local cultivars and entries representing a greater diversity of resistance genes. The virulence phenotype(s) for populations of H. avenae in the PNW did not correspond to any of the 11 pathotypes defined by the Test Assortment. Five PNW populations exhibited affinities with Group 2 but were not defined by pathotypes Ha12 and Ha22. Reproduction was prevented or greatly inhibited by barley carrying the Rha3 resistance gene and by most carriers of Rha2 resistance, and by selected oat cultivars with multigenic resistance. Wheat cultivars carrying the Cre1 resistance gene were highly effective in suppressing H. avenae reproduction. Current PNW wheat cultivars do not carry the Cre1 resistance gene. Crosses between Ouyen, an Australian bread wheat with Cre1 resistance, and several PNW wheat cultivars were resistant. The CreR gene also prevented H. avenae reproduction in the trial where it was tested. Intermediate levels of reproduction occurred on wheat cultivars carrying the Cre5, Cre7 and Cre8 resistance genes, each of which was considered useful for pyramiding into cultivars with Cre1 resistance. This research identified genetic resources of value in PNW cereal crop breeding programmes.

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Safari, E., N. N. Gororo, R. F. Eastwood, J. Lewis, H. A. Eagles, and F. C. Ogbonnaya. "Impact of Cre1, Cre8 and Cre3 genes on cereal cyst nematode resistance in wheat." Theoretical and Applied Genetics 110, no. 3 (January 18, 2005): 567–72. http://dx.doi.org/10.1007/s00122-004-1873-8.

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Mountfort, Katrina, Didier Carrié, Marco Valgimigli, Gennaro Sardella, Shmuel Banai, Rafael Romaguera, and Pieter Stella. "Meeting the Unmet – The Cre8 Polymer-free Drug-eluting Stents Technology." Interventional Cardiology Review 9, no. 3 (2014): 184. http://dx.doi.org/10.15420/icr.2014.9.3.184.

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The use of first-generation drug-eluting stents (DES) has been associated with safety concerns such as very late stent thrombosis. Today, with the release of newer DES, there is a need for comparative studies of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) to demonstrate their value in patients with high risk of restenosis such as diabetic patients. In a satellite symposium presented at EuroPCR 2014, the Cre8™ DES was discussed. The Cre8 device has a number of unique clinical features, including polymer-free technology, abluminal reservoir technology and bio-inducer surface that ensure effective neointima suppression and rapid endothelialisation. The efficacy of the Cre8 DES has been demonstrated in the International randomised comparison between DES Limus Carbostent and Taxus drug-eluting stents in the treatment of de novo coronary lesions (NEXT) randomised clinical study, with equivalent efficacy in the diabetic and general populations, a unique finding. Ongoing clinical studies such as Investig8 and the Tel Aviv Medical Center (TLVMC) Cre8 study have confirmed the efficacy of the device in patient populations with a high proportion of diabetic patients. The Demonstr8 randomised trial has shown almost complete Cre8 strut coverage at three months with a numerical advantage versus bare metal stent (bare metal stents [BMS] – comparator device) at one month. In addition, use of the Cre8 DES may enable a shorter duration of dual antiplatelet therapy (DAPT) following PCI. The Cre8 DES therefore represents a significant advance in stent technology and may be particularly useful in challenging clinical settings

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Romaguera, Rafael, Pablo Salinas, Josep Gomez-Lara, Salvatore Brugaletta, Antonio Gómez-Menchero, Miguel A. Romero, Sergio García-Blas, et al. "Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial." European Heart Journal 43, no. 13 (December 10, 2021): 1320–30. http://dx.doi.org/10.1093/eurheartj/ehab790.

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Abstract Aim Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. Methods and results We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44–0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46–0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. Conclusion In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome. Clinical trial registration ClinicalTrials.gov: NCT03321032.

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Carrié, Didier. "The Use of the Cre8 Stent in Patients with Diabetes Mellitus." Interventional Cardiology Review 11, no. 1 (2016): 47. http://dx.doi.org/10.15420/icr.2016.11.01.47.

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Despite improved clinical outcomes following the availability of second-generation drug eluting stents (DES), percutaneous coronary intervention (PCI) is associated with worse clinical and angiographic outcomes among patients with diabetes mellitus (DM) than among non-diabetics. The Cre8™ Amphilimus-eluting DES is polymer-free, resulting in a reduced inflammatory response and lower risk of stent thrombosis. It showed equivalent efficacy and safety in diabetic and non-diabetic populations, a unique finding among DES studies. These findings were confirmed in a real-world study called INVESTIG8. Another real-world study, pARTicip8, is ongoing. The RESERVOIR clinical trial recruited patients with diabetes mellitus and showed noninferiority of the Cre8 DES compared to an everolimus-eluting DES but showed a statistical superiority of Cre8 in diabetic patients with higher metabolic dysfunctions. The Cre8 DES is therefore a valuable option for this important patient population.

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Carrié, Didier. "The Use of the Cre8 Stent in Patients with Diabetes Mellitus." Interventional Cardiology Review 11, no. 1 (2016): 47. http://dx.doi.org/10.15420/icr.2016.11.1.47.

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Despite improved clinical outcomes following the availability of second-generation drug eluting stents (DES), percutaneous coronary intervention (PCI) is associated with worse clinical and angiographic outcomes among patients with diabetes mellitus (DM) than among non-diabetics. The Cre8™ Amphilimus-eluting DES is polymer-free, resulting in a reduced inflammatory response and lower risk of stent thrombosis. It showed equivalent efficacy and safety in diabetic and non-diabetic populations, a unique finding among DES studies. These findings were confirmed in a real-world study called INVESTIG8. Another real-world study, pARTicip8, is ongoing. The RESERVOIR clinical trial recruited patients with diabetes mellitus and showed noninferiority of the Cre8 DES compared to an everolimus-eluting DES but showed a statistical superiority of Cre8 in diabetic patients with higher metabolic dysfunctions. The Cre8 DES is therefore a valuable option for this important patient population.

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Moatamedi, Marzieh, Eidi Bazgir, Mehdi Nasr Esfahani, and Mostafa Darvishnia. "Genetic variation of bread wheat accessions in response to the cereal cyst nematode, Heterodera filipjevi." Nematology 20, no. 9 (2018): 859–75. http://dx.doi.org/10.1163/15685411-00003181.

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Summary Bread wheat, Triticum aestivum, produces large edible grains and is consumed by 75% of the world’s populations. Cereal cyst nematodes have a global distribution and cause significant economic yield losses in many countries. Therefore, there is an urgent need to identify new resistance sources. In this study, the genetic diversity of 43 wheat accessions in response to cereal cyst nematode, Heterodera filipjevi Isfahan pathotype, was assessed using a simple sequence repeat (SSR) marker. Seven primers were used, out of which five primers showed polymorphisms. Alleles per primer varied from one to three per locus (mean 2.85). The highest and lowest polymorphic information content of 0.81 and 0.44 (mean 0.66) were related to Xgwm 3012DL and Xgwm147, respectively. Genetic similarity was 29-88% between accessions. SSR analysis divided the accessions into five main groups. Resistant cultivars ‘Bam’ and ‘Behrang’ possessed both Cre1 and Cre8 resistant genes. The Cre3 and Cat genes were partially sequenced in five cultivars of different responses to H. filipjevi. The nucleotide sequences were compared to Cre3 and Cat homologues, indicating 93-100% and 86-92% homology, respectively. The MEGA program showed highest similarity of Cre3 and Cat genes amplified with the resistance gene analogues (RGA14) in the wheat and Cat3-A1 gene in ‘Carnamah’. This research showed that SRR markers could efficiently verify genetic diversity between wheat accessions, and the known resistance genes (Cre genes) against the cereal cyst nematodes could not control the H. filipjevi Isfahan pathotype populations, except the Cre1 gene.

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Manna, PR, DW Eubank, E. Lalli, P. Sassone-Corsi, and DM Stocco. "Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1." Journal of Molecular Endocrinology 30, no. 3 (June 1, 2003): 381–97. http://dx.doi.org/10.1677/jme.0.0300381.

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Transcriptional induction by cAMP is mediated through the interaction of the cAMP response-element binding protein (CREB) with a cAMP response element (CRE) in the promoter of target genes. The steroidogenic acute regulatory (StAR) protein gene is regulated by cAMP-mediated signaling in steroidogenic cells even though its promoter lacks a consensus CRE. Previously, we have identified three highly conserved 5'-CRE half-sites within the -96/-67 bp region of the mouse StAR gene, and a member of the CREB family (CREB/CRE modulator (CREM)) was shown to be involved in its expression and regulation. Here we show that CREB and CREMtau (but not CREMalpha and CREMbeta) have qualitatively similar effects on StAR promoter activity in response to (Bu)(2)cAMP. Studies on the effects of the functional integrity of the CRE half-sites on CREB-dependent (Bu)(2)cAMP-mediated StAR gene transcription demonstrated the greater importance of the CRE2 site in comparison with the CRE1 and CRE3 sites. The CRE2 sequence was also found to bind specifically to recombinant CREB protein and nuclear extract from MA-10 mouse Leydig tumor cells. The cAMP and CREB/CREM responsive region (-151/-1 bp) of the mouse StAR promoter also contains three recognition motifs for steroidogenic factor 1 (SF-1). Electrophoretic mobility shift assays and reporter gene analyses demonstrated the involvement of different SF-1 elements in StAR gene expression with the order of importance being SF-1/3>SF-1/1>SF-1/2. Specific mutations that eliminated the binding sites of CRE and SF-1 elements, either alone or in combination, resulted in an attenuation of StAR promoter activity, indicating that CREB and SF-1 can regulate StAR gene transcription in a cooperative fashion. In addition, mammalian two-hybrid assays revealed a high affinity protein-protein interaction between CREB/CREMtau and SF-1 which appeared to be dependent upon CREB protein phosphorylation. These findings further demonstrate CREB's role in StAR gene transcription and also provide evidence that the combined action of CREB/CREMtau and SF-1 results in enhanced activation of the StAR promoter.

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Mountfort, Katrina, David Antoniucci, Roxana Mehran, Giuseppe DeLuca, Holger Nef, Mathias Vrolix, and Ahmed Khashaba. "Cre8™ Unique Technology in Challenging Daily Practice." Interventional Cardiology Review 9, no. 3 (2014): 180. http://dx.doi.org/10.15420/icr.2014.9.3.180.

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The use of drug-eluting stents (DES) has improved clinical outcomes in percutaneous coronary intervention (PCI) procedures. However, first-generation DES were associated with safety concerns arising from the persistence of durable polymers, including late stent thrombosis. The Cre8™ DES is a novel polymer-free stent designed to overcome these issues. In a presentation at EuroPCR 2014, two clinical cases were discussed. The first was a case of high bleeding risk; the second was the case of multivessel disease with a significant risk of stent restenosis. Together, these cases illustrated the complexity of decision-making in PCI in daily practice. In both cases, the Cre8™ DES offered a safe and effective solution to these challenging cases.

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Tigkiropoulos, Konstantinos, Manolis Abatzis-Papadopoulos, Katerina Sidiropoulou, Kyriakos Stavridis, Dimitrios Karamanos, Ioannis Lazaridis, and Nikolaos Saratzis. "Polymer Free Amphilimus Drug Eluting Stent for Infrapopliteal Arterial Disease in Patients with Critical Limb Ischemia: A New Device in the Armamentarium." Medicina 59, no. 1 (December 24, 2022): 39. http://dx.doi.org/10.3390/medicina59010039.

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Background and Objectives: Endovascular technologies have significantly improved the outcome of patients with critical limb ischemia (CLI). Drug eluting stents (DES) have documented their efficacy against percutaneous transluminal angioplasty (PTA) and bare metal stents (BMS) in infrapopliteal arterial occlusive disease. However, late in-stent neoatherosclerosis may lead to vascular lumen loss and eventually thrombosis. Polymer free DES constitute a new technology aiming to improve long term patency which their action is still under investigation. The purpose of this study is to report the mechanism of action and to provide a literature review of a novel polymer free amphilimus eluting stent (Cre8, Alvimedica, Instabul, Turkey) in infrapopliteal arterial disease. Methods: Publications listed in electronic databases, European Union Drug Regulating Authorities Clinical Trials Database, as well as scientific programmes of recent interventional vascular conferences were searched. Three studies were included. We analyzed primary and secondary patency, major amputation rate, freedom from CD-TLR, and mortality. Results: Cre8 was implanted in 79 patients with CLI. Most of the patients (n = 65) were Rutherford class 5–6 (82.3%), and diabetes mellitus (DM) was present in 66 patients (83.5%). Mean primary patency was 82.5% at 12 months. Mean lesion stented length was 20 mm and 35 mm in two studies. Mean limb salvage was 91.3% at 12 months. Freedom from CD-TLR was reported in two out of the three studies and was 96% and 83.8%. Mortality was 15% and 23.8% in the same studies, whilst it was not reported in one study. Conclusion: Stenting of infrapopliteal arteries with Cre8 is safe and feasible in patients with CLI and diabetes. All studies have shown very good primary patency and freedom from CD-TLR at 12 and 24 months. Larger observational prospective studies and randomized trials are necessary to establish long term effectiveness and clinical outcomes using the non-polymer Cre8 DES.

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Mehran, Roxana, Antonio Colombo, Pieter Stella, Rafael Romaguera, and Gennaro Sardella. "Patient-tailored Drug-eluting Stent Choice – A Solution for Patients with Diabetes." Interventional Cardiology Review 10, no. 3 (2015): 158. http://dx.doi.org/10.15420/icr.2015.10.03.158.

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Although second-generation drug-eluting stents (DES) have improved outcomes in percutaneous coronary interventions (PCIs), important unmet needs remain. Two symposia at EuroPCR 2015 focused on two challenging scenarios. First, patients with diabetes mellitus (DM) have generally inferior outcomes following PCI. The Cre8™ stent (manufactured by CID Spa, member of Alvimedica Group) has shown unique efficacy in subpopulations of patients with DM during clinical trials. A live case in a patient with diabetes illustrated the challenges of complex multivessel disease. Second, optimising stent selection towards devices that have demonstrated complete and early endothelialisation offers the potential to reduce the duration of dual antiplatelet therapy. The Cre8™ DES features a polymer-free platform and has been associated with low rates of in-stent thrombosis.

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A Byrne, Robert, Eric Eeckhout, Gennaro Sardella, Pieter Stella, and Stefan Verheye. "PCI in Patients with Diabetes: Role of the Cre8 Drug-eluting Stent." Interventional Cardiology Review 12, no. 01 (2017): 13. http://dx.doi.org/10.15420/icr.2016:28:2.

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Patients with diabetes have poor outcomes compared to the general patient population when undergoing percutaneous coronary intervention. The Cre8™ (Alvimedica) drug-eluting stent (DES) has unique features that may improve clinical outcomes in patients with diabetes. These include abluminal reservoir technology, a proprietary polymer-free drug-release system consisting of reservoirs on the stent’s outer surface that control and direct drug release exclusively towards the vessel wall, and the Amphilimus™ formulation, which enables enhanced drug tissue permeation, utilising fatty acid transport pathways. This is particularly advantageous in diabetic patients, since increased uptake of fatty acid occurs in diabetic cells. Furthermore, mTOR inhibitors (-limus drugs), which are utilised in DESs, are relatively ineffective in diabetic cells. Clinical efficacy and safety of the Cre8™ in patients with diabetes has been demonstrated in a number of clinical trials and real-world studies, and further studies are on-going.

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Giglioli, Cristina, Emanuele Cecchi, Chiara Formentini, Marco Chiostri, Niccolò Marchionni, and Salvatore Mario Romano. "Malapposed Struts with Cre8, Biomatrix, and Xience Stents Assessed with OCT Immediately after Implantation and at 6-Month Follow-Up: Can the Different Biomechanical Characteristics of the Three Stents Impact on Struts Malapposition?" Journal of Interventional Cardiology 2021 (April 9, 2021): 1–9. http://dx.doi.org/10.1155/2021/6611486.

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Background. Although the clinical effects of stent malapposition remain controversial, several analyses of stent registries consistently have found that malapposed struts were frequently identified in patients who experienced stent thrombosis. In this study, which is a subanalysis of the previously published CREBX-OCT study, we compared optical coherence tomography (OCT) analysis at the index percutaneous coronary intervention (PCI) and at six-month follow-up in 37 patients randomly assigned to receive, by a single operator, three different second-generation drug-eluting stents (Cre8, Biomatrix, and Xience) aiming to clarify if the malapposition observed at six-month follow-up was persistent or late-acquired. Moreover, we investigated if there were some differences in the behavior of the three different kinds of stents in relation to the struts malapposition. Material and Methods. We analyzed 614 and 599 cross sections and 5514 and 5377 struts at the index PCI and at six-month follow-up, respectively. The qualitative analysis of the plaque composition among the three groups did not show significant differences. Results. The lumen area did not significantly change from the index procedure to the six-month follow-up in the three groups; on the contrary, the number of malapposed struts increased significantly in the Cre8 and Biomatrix groups but not in the Xience group: 0.58 ± 1.51 and 3.29 ± 5.33 ( p < 0.023 ) in the Cre8 group, 0.55 ± 1.81 and 1.73 ± 2.28 ( p < 0.024 ) in the Biomatrix group, and 0.55 ± 1.5 and 0.25 ± 0.87 ( p < 0.166 ) in the Xience group, respectively. Conclusions. Therefore, the malapposition observed at six-month follow-up in our study population could be mainly considered as acquired and attributable to biomechanical reasons due to the structural differences among the three stents. This trial is registered with Clinical Trials.gov Identifier: NCT02850497.

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Manna, Pulak R., and Douglas M. Stocco. "Crosstalk of CREB and Fos/Jun on a single cis-element: transcriptional repression of the steroidogenic acute regulatory protein gene." Journal of Molecular Endocrinology 39, no. 4 (October 2007): 261–77. http://dx.doi.org/10.1677/jme-07-0065.

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AbstractTranscriptional regulation of the steroidogenic acute regulatory (StAR) protein gene by cAMP-dependent mechanisms occurs in the absence of a consensus cAMP-response element (CRE; TGACGTCA) and is mediated by several sequence-specific transcription factors. We previously identified three CRE-like sites (within the −151/−1 bp cAMP-responsive region of the mouse StAR gene), of which the CRE2 site overlaps with an activator protein-1 (AP-1) motif (TGACTGA, designated as CRE2/AP-1) that can bind both CRE and AP-1 DNA-binding proteins. The present studies were aimed at exploring the functional crosstalk between CREB (CRE-binding protein) and cFos/cJun (AP-1 family members) on the CRE2/AP-1 element and its role in regulating transcription of the StAR gene. Using MA-10 mouse Leydig tumor cells, we demonstrate that the CRE and AP-1 families of proteins interact with the CRE2/AP-1 sequence. CREB, cFos, and cJun proteins were found to bind to the CRE2/AP-1 motif but not the CRE1 and CRE3 sites. Treatment with the cAMP analog (Bu)2cAMP augmented phosphorylation of CREB (Ser133), cFos (Thr325), and cJun (ser73). Chromatin immunoprecipitation studies revealed that the induction of CREB, cFos, and cJun by (Bu)2cAMP was correlated with protein–DNA interactions and recruitment of the coactivator CREB-binding protein (CBP) to the StAR promoter. EMSA studies employing CREB and cFos/cJun proteins demonstrated competition between these factors for binding to the CRE2/AP-1 motif. Transfection of cells containing the −151/−1 StAR reporter with CREB and cFos/cJun resulted in trans-repression of the StAR gene, an event tightly associated with CBP, demonstrating that both CREB and Fos/Jun compete with each other for binding with limited amounts of intracellular CBP. Overexpression of adenovirus E1A, which binds and inactivates CBP, markedly suppressed StAR gene expression. Ectopic expression of CBP eliminated the repression of the StAR gene by E1A and potentiated the activity of CREB and cFos/cJun on StAR promoter responsiveness. These findings identify molecular events involved in crosstalk between CREB and cFos/cJun, which confer both gain and loss of function on a single cis-element in fine-tuning of the regulatory events involved in transcription of the StAR gene.

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Byrne, Robert A., Shmuel Banai, Roisin Colleran, and Antonio Colombo. "Challenges in Patients with Diabetes: Improving Clinical Outcomes After Percutaneous Coronary Intervention Through EVOlving Stent Technology." Interventional Cardiology Review 13, no. 01 (2017): 40. http://dx.doi.org/10.15420/icr.2017:27:1.

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Patients with diabetes have poorer outcomes after percutaneous coronary intervention than patients without diabetes. The Cre8™ EVO drug-eluting stent (DES) has design features that aim to improve clinical outcomes in patients with diabetes. These include Abluminal Reservoir Technology – a proprietary polymer-free drug-release system consisting of reservoirs on the abluminal surface of the stent that control drug release and direct the drug exclusively towards the vessel wall – and the Amphilimus™ drug formulation, which enables enhanced drug—tissue permeation utilising fatty acid transport pathways. The latter is particularly advantageous in patients with diabetes, whose cell metabolism favours increased cellular uptake of fatty acid. Furthermore, evidence suggests that mTOR inhibitors (-limus drugs) utilised in conventional DES are less effective in diabetic cells. The new stent architecture provides high device deliverability and conformability, facilitating clinical use in complex disease patterns and high-risk lesion morphologies. Clinical evidence for the efficacy and safety of the Cre8™ DES in patients with diabetes has been demonstrated in a number of clinical trials and observational registries. These data are reviewed herein, along with an overview of on-going randomised trials.

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Williams, K. J., J. G. Lewis, P. Bogacki, M. A. Pallotta, K. L. Willsmore, H. Kuchel, and H. Wallwork. "Mapping of a QTL contributing to cereal cyst nematode tolerance and resistance in wheat." Australian Journal of Agricultural Research 54, no. 8 (2003): 731. http://dx.doi.org/10.1071/ar02225.

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Cereal cyst nematode (CCN; Heterodera avenae Woll.) is a root pathogen of cereals that can cause severe yield losses in intolerant wheat cultivars. Tolerance to CCN, measured as early vigour in CCN-infested plots, was mapped in a Trident/Molineux doubled-haploid (DH) population. A locus accounting for a significant proportion of the tolerance to CCN was mapped to chromosome 6B of Molineux by association with RFLP loci Xcdo347-6B and Xbcd1 and also by nullisomic/tetrasomic substitution line analysis, and has been designated Cre8. The linkage of CCN tolerance with Xcdo347-6B was validated using a Barunga/Suneca DH population. The Cre8 locus also contributed to CCN resistance in the Trident/Molineux population. The RFLP locus Xbcd175, which is diagnostic for the Aegilops ventricosa segment VPM1 of Trident, explained up to 18% of the variation for early vigour in CCN-infested soils in the Trident/Molineux population. However, the Trident/Molineux population also segregated for early vigour in the absence of CCN, with Xbcd175 explaining up to 7% of the variation for this trait. The VPM1 segment of Trident therefore provides early vigour that may contribute to CCN tolerance in this cultivar.

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Cariss, S. James L., Amy E. Tayler, and Matthew B. Avison. "Defining the Growth Conditions and Promoter-Proximal DNA Sequences Required for Activation of Gene Expression by CreBC in Escherichia coli." Journal of Bacteriology 190, no. 11 (March 28, 2008): 3930–39. http://dx.doi.org/10.1128/jb.00108-08.

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ABSTRACT CreBC is a two-component system that controls the expression of a number of genes in Escherichia coli (called the cre regulon) that encode diverse functions, including intermediary metabolic enzymes. Using a reporter construct, we have shown that cre regulon gene expression is activated during growth in minimal media when glycolytic carbon sources are being fermented. It also is activated during aerobic growth when fermentation products are being used as carbon sources. CreB and CreC are essential for the activation of cre regulon gene expression, but CreA and CreD, encoded as part of the creABCD gene cluster, are not. CreB binds to a TTCACnnnnnnTTCAC direct repeat (the cre tag) in vitro, and this sequence, which is associated with cre regulon gene promoters, is required for the control of gene expression in vivo. These observations support the hypothesis that CreBC is a functional two-component system involved in the metabolic control of transcription in E. coli and confirm that CreB is a DNA binding transcriptional regulator.

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Gibbs, O., J. Assad, A. Faour, T. Ang, J. Xu, R. Rajaratnam, D. Leung, et al. "Clinical Outcomes of Cre8 Coronary Stent in Complex Percutaneous Coronary Intervention." Heart, Lung and Circulation 27 (2018): S442—S443. http://dx.doi.org/10.1016/j.hlc.2018.06.904.

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Ogbonnaya, F. C., N. C. Subrahmanyam, O. Moullet, J. de Majnik, H. A. Eagles, J. S. Brown, R. F. Eastwood, J. Kollmorgen, R. Appels, and E. S. Lagudah. "Diagnostic DNA markers for cereal cyst nematode resistance in bread wheat." Australian Journal of Agricultural Research 52, no. 12 (2001): 1367. http://dx.doi.org/10.1071/ar01031.

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The development of cultivars resistant to cereal cyst nematode (CCN) is a primary objective in wheat breeding in the southern wheatbelt of Australia. Nine CCN resistance genes have been identified in wheat and its relatives, some of which confer resistance to the Australian pathotype of CCN (Ha13). Cultivars released in Australia with CCN resistance carry either the Cre1 or CreF gene, with the Cre3 gene present in advanced breeding lines. The biological assay for CCN resistance screening in wheat is time-consuming, not reliable on a single-plant basis, and prone to inconsistencies, thus reducing the efficiency of selection amongst breeding lines. Using gene sequences initially isolated from the Cre3 locus, a DNA-based marker selection system was developed and applied to unambiguously identify wheat lines carrying resistance alleles at theCre1 and/or Cre3 loci in breeding populations derived from diverse genetic backgrounds. Homologues of sequences from the Cre3 locus, located elsewhere in the wheat genome, can also be used to select wheat lines with a newly identified CCN resistance gene (Cre6) introgressed from Aegilops ventricosa. Application of these markers has become an integral part of the southern Australian breeding programs.

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Manna, Pulak R., Matthew T. Dyson, Darrell W. Eubank, Barbara J. Clark, Enzo Lalli, Paolo Sassone-Corsi, Anthony J. Zeleznik, and Douglas M. Stocco. "Regulation of Steroidogenesis and the Steroidogenic Acute Regulatory Protein by a Member of the cAMP Response-Element Binding Protein Family." Molecular Endocrinology 16, no. 1 (January 1, 2002): 184–99. http://dx.doi.org/10.1210/mend.16.1.0759.

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Abstract The mitochondrial phosphoprotein, the steroidogenic acute regulatory (StAR) protein, is an essential component in the regulation of steroid biosynthesis in adrenal and gonadal cells through cAMP-dependent pathways. In many cases transcriptional induction by cAMP is mediated through the interaction of a cAMP response-element binding protein (CREB) family member with a consensus cAMP response element (CRE; 5′-TGACGTCA-3′) found in the promoter of target genes. The present investigation was carried out to determine whether a CRE-binding protein (CREB) family member [CREB/CRE modulator (CREM) family] was involved in the regulation of steroidogenesis and StAR protein expression. Transient expression of wild- type CREB in MA-10 mouse Leydig tumor cells further increased the levels of (Bu)2cAMP-induced progesterone synthesis, StAR promoter activity, StAR mRNA, and StAR protein. These responses were significantly inhibited by transfection with a dominant-negative CREB (A-CREB), or with a CREB mutant that cannot be phosphorylated (CREB-M1), the latter observation indicating the importance of phosphorylation of a CREB/CREM family member in steroidogenesis and StAR expression. The CREB/CREM-responsive region in the mouse StAR gene was located between −110 and −67 bp upstream of the transcriptional start site. An oligonucleotide probe (−96/−67 bp) containing three putative half-sites for 5′-canonical CRE sequences (TGAC) demonstrated the formation of protein-DNA complexes in EMSAs with recombinant CREB protein as well as with nuclear extracts from MA-10 or Y-1 mouse adrenal tumor cells. The predominant binding factor observed with EMSA was found to be the CREM protein as demonstrated using specific antibodies and RT-PCR analyses. The CRE elements identified within the− 96/−67 bp region were tested for cAMP responsiveness by generating mutations in each of the CRE half-sites either alone or in combination. Although each of the CRE sites contribute in part to the CREM response, the CRE2 appears to be the most important site as determined by EMSA and by reporter gene analyses. Binding specificity was further assessed using specific antibodies to CREB/CREM family members, cold competitors, and mutations in the target sites that resulted in either supershift and/or inhibition of these complexes. We also demonstrate that the inducible cAMP early repressor markedly diminished the endogenous effects of CREM on cAMP-induced StAR promoter activity and on StAR mRNA expression. These are the first observations to provide evidence for the functional involvement of a CREB/CREM family member in the acute regulation of trophic hormone-stimulated steroidogenesis and StAR gene expression.

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Zaky, F., M. Rooney, M. Ghodsian, and P. Shetty. "The CRE8 Polymer-free Amphilimus-eluting Coronary Stent. Real World Data from a Tertiary Hospital." Heart, Lung and Circulation 28 (2019): S430. http://dx.doi.org/10.1016/j.hlc.2019.06.696.

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Rozemeijer, Rik, Mera Stein, Michiel Voskuil, Adriaan Kraaijeveld, Leo Timmers, Ramon Rodríguez-Olivares, Saskia Rittersma, and Pieter Stella. "TCT-267 Clinical outcomes of diabetic patients treated with an amphilimus-eluting stent and a short duration of dual antiplatelet therapy in routine clinical practice: first results of the Utrecht Cre8 (U-Cre8) Registry." Journal of the American College of Cardiology 68, no. 18 (November 2016): B109. http://dx.doi.org/10.1016/j.jacc.2016.09.396.

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Pivato, Carlo A., Pier Pasquale Leone, Gennaro Petriello, Jorge Sanz-Sanchez, Mauro Chiarito, and Giulio G. Stefanini. "The Cre8 amphilimus-eluting stent for the treatment of coronary artery disease: safety and efficacy profile." Expert Review of Medical Devices 17, no. 4 (March 18, 2020): 267–75. http://dx.doi.org/10.1080/17434440.2020.1740587.

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Santos, África Duque, Andrés Reyes Valdivia, Cristina Gómez Olmos, Julia Ocaña Guaita, and Claudio Gandarias Zúñiga. "LEA 29. Initial Experience With Cre8 Stent for Below-Knee Disease in Patients With Critical Limb Ischemia." Journal of Vascular Surgery 70, no. 5 (November 2019): e126. http://dx.doi.org/10.1016/j.jvs.2019.08.046.

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Craig, Johanna C., Maria A. Schumacher, Steven E. Mansoor, David L. Farrens, Richard G. Brennan, and Richard H. Goodman. "Consensus and Variant cAMP-regulated Enhancers Have Distinct CREB-binding Properties." Journal of Biological Chemistry 276, no. 15 (December 27, 2000): 11719–28. http://dx.doi.org/10.1074/jbc.m010263200.

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Recent determination of the cAMP response element-binding protein (CREB) basic leucine zipper (bZIP) consensus CRE crystal structure revealed key dimerization and DNA binding features that are conserved among members of the CREB/CREM/ATF-1 family of transcription factors. Dimerization appeared to be mediated by a Tyr307–Glu312interhelical hydrogen bond and a Glu319–Arg314electrostatic interaction. An unexpected hexahydrated Mg2+ion was centered above the CRE in the dimer cavity. In the present study, we related these features to CREB dimerization and DNA binding. A Y307F substitution reduced dimer stability and DNA binding affinity, whereas a Y307R mutation produced a stabilizing effect. Mutation of Glu319to Ala or Lys attenuated dimerization and DNA binding. Mg2+ions enhanced the binding affinity of wild-type CREB to the palindromic CRE by ∼20-fold but did not do so for divergent CREs. Similarly, mutation of Lys304, which mediates the CREB interaction with the hydrated Mg2+, blocked CREB binding to the palindromic but not the variant CRE sequences. The distinct binding characteristics of the K304A mutants to the consensus and variant CRE sequences indicate that CREB binding to these elements is differentially regulated by Mg2+ions. We suggest that CREB binds the consensus and variant CRE sequences through fundamentally distinct mechanisms.

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Nagar, K., P. Pender, J. Leung, A. Hopkins, D. Leung, R. Rajaratnam, C. Juergens, T. Badie, and S. Lo. "Long-Term Outcomes in Chronic Total Occlusion (CTO) Percutaneous Coronary Intervention (PCI) with Cre8 Stents: A Single-Centre Registry." Heart, Lung and Circulation 30 (2021): S312. http://dx.doi.org/10.1016/j.hlc.2021.06.488.

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Norman, S., Zaki N. Mohd, A. Lee, and P. Shetty. "The CRE8 Amphilimus Coronary Stent: Safety and Efficacy in a Real-World Population of Diabetic and Non-Diabetic Patients." Heart, Lung and Circulation 30 (2021): S321. http://dx.doi.org/10.1016/j.hlc.2021.06.505.

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Moretti, Claudio, Vasco Lolli, Giovanni Perona, Maria-Cristina Vignolini, Karine Cabiale, Mimmo Falzone, and Marco Galloni. "Cre8™ coronary stent: preclinical in vivo assessment of a new generation polymer-free DES with Amphilimus™ formulation." EuroIntervention 7, no. 9 (January 2012): 1087–94. http://dx.doi.org/10.4244/eijv7i9a173.

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Martínez-Castro, Daniel, Shailendra Kumar, José Luis Flores Rojas, Aldo Moya-Álvarez, Jairo M. Valdivia-Prado, Elver Villalobos-Puma, Carlos Del Castillo-Velarde, and Yamina Silva-Vidal. "The Impact of Microphysics Parameterization in the Simulation of Two Convective Rainfall Events over the Central Andes of Peru Using WRF-ARW." Atmosphere 10, no. 8 (August 1, 2019): 442. http://dx.doi.org/10.3390/atmos10080442.

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The present study explores the cloud microphysics (MPs) impact on the simulation of two convective rainfall events (CREs) over the complex topography of Andes mountains, using the Weather Research and Forecasting- Advanced Research (WRF-ARW) model. The events occurred on December 29 2015 (CRE1) and January 7 2016 (CRE2). Six microphysical parameterizations (MPPs) (Thompson, WSM6, Morrison, Goddard, Milbrandt and Lin) were tested, which had been previously applied in complex orography areas. The one-way nesting technique was applied to four domains, with horizontal resolutions of 18, 6, and 3 km for the outer ones, in which cumulus and MP parameterizations were applied, while for the innermost domain, with a resolution of 0.75 km, only MP parameterization was used. It was integrated for 36 h with National Centers for Environmental Prediction (NCEP Final Operational Global Analysis (NFL) initial conditions at 00:00 UTC (Coordinated Universal Time). The simulations were verified using Geostationary Operational Environmental Satellites (GOES) brightness temperature, Ka band cloud radar, and surface meteorology variables observed at the Huancayo Observatory. All the MPPs detected the surface temperature signature of the CREs, but for CRE2, it was underestimated during its lifetime in its vicinity, matching well after the simulated event. For CRE1, all the schemes gave good estimations of 24 h precipitation, but for CRE2, Goddard and Milbrandt underestimated the 24 h precipitation in the inner domain. The Morrison and Lin configurations reproduced the general dynamics of the development of cloud systems for the two case studies. The vertical profiles of the hydrometeors simulated by different schemes showed significant differences. The best performance of the Morrison scheme for both case studies may be related to its ability to simulate the role of graupel in precipitation formation. The analysis of the maximum reflectivity field, cloud top distribution, and vertical structure of the simulated cloud field also shows that the Morrison parameterization reproduced the convective systems consistently with observations.

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Fink, Martina, Jure Ačimovič, Tadeja Režen, Nataša Tanšek, and Damjana Rozman. "Cholesterogenic Lanosterol 14α-Demethylase (CYP51) Is an Immediate Early Response Gene." Endocrinology 146, no. 12 (December 1, 2005): 5321–31. http://dx.doi.org/10.1210/en.2005-0781.

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Lanosterol 14α-demethylase (CYP51) responds to cholesterol feedback regulation through sterol regulatory element binding proteins (SREBPs). The proximal promoter of CYP51 contains a conserved region with clustered regulatory elements: GC box, cAMP-response elements (CRE-like), and sterol regulatory element (SRE). In lipid-rich (SREBP-poor) conditions, the CYP51 mRNA drops gradually, the promoter activity is diminished, and no DNA-protein complex is observed at the CYP51-SRE1 site. The majority of cAMP-dependent transactivation is mediated through a single CRE (CYP51-CRE2). Exposure of JEG-3 cells to forskolin, a mediator of the cAMP-dependent signaling pathway, provokes an immediate early response of CYP51, which has not been described before for any cholesterogenic gene. The CYP51 mRNA increases up to 4-fold in 2 h and drops to basal level after 4 h. The inducible cAMP early repressor (ICER) is involved in attenuation of transcription. Overexpressed CRE-binding protein (CREB)/CRE modulator (CREM) transactivates the mouse/human CYP51 promoters containing CYP51-CRE2 independently of SREBPs, and ICER decreases the CREB-induced transcription. Besides the increased CYP51 mRNA, forskolin affects the de novo sterol biosynthesis in JEG-3 cells. An increased consumption of lanosterol, a substrate of CYP51, is observed together with modulation of the postlanosterol cholesterogenesis, indicating that cAMP-dependent stimuli cross-talk with cholesterol feedback regulation. CRE-2 is essential for cAMP-dependent transactivation, whereas SRE seems to be less important. Interestingly, when CREB is not limiting, the increasing amounts of SREBP-1a fail to transactivate the CYP51 promoter above the CREB-only level, suggesting that hormones might have an important role in regulating cholesterogenesis in vivo.

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BRATKE, Jutta, Thomas KIETZMANN, and Kurt JUNGERMANN. "Identification of an oxygen-responsive element in the 5′-flanking sequence of the rat cytosolic phosphoenolpyruvate carboxykinase-1 gene, modulating its glucagon-dependent activation." Biochemical Journal 339, no. 3 (April 26, 1999): 563–69. http://dx.doi.org/10.1042/bj3390563.

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The glucagon-stimulated transcription of the cytosolic phosphoenolpyruvate carboxykinase-1 (PCK1) gene is mediated by cAMP and positively modulated by oxygen in primary hepatocytes. Rat hepatocytes were transfected with constructs containing the first 2500, 493 or 281 bp of the PCK1 5ʹ-flanking region in front of the chloramphenicol acetyltransferase (CAT) reporter gene. With all three constructs glucagon induced CAT activity with decreasing efficiency maximally under arterial pO2 and to about 65% under venous pO2. Rat hepatocytes were then transfected with constructs containing the first 493 bp of the PCK1 5ʹ-flanking region in front of the luciferase (LUC) reporter gene, which were block-mutated at the CRE1 (cAMP-response element-1; -93/-86), putative CRE2 (-146/-139), promoter element (P) 1 (-118/-104), P2 (-193/-181) or P4 (-291/-273) sites. Glucagon induced LUC activity strongly when the P1 and P2 sites were mutated and weakly when the P4 site was mutated; induction of the P1, P2 and P4 mutants was positively modulated by the pO2. Glucagon also induced LUC activity strongly when the putative CRE2 site was altered; however, induction of the CRE2 mutant was not modulated by the pO2. Glucagon did not induce LUC activity when the CRE1 site was modified. These experiments suggested that the CRE1 but not the putative CRE2 was an essential site necessary for the cAMP-mediated PCK1 gene activation by glucagon and that the putative CRE2 site was involved in the oxygen-dependent modulation of PCK1 gene activation. To confirm these conclusions rat hepatocytes were transfected with simian virus 40 (SV40)-promoter-driven LUC-gene constructs containing three CRE1 sequences (-95/-84), three CRE2 sequences (-148/-137) or three CRE1 sequences plus two CRE2 sequences of the PCK1 gene in front of the SV40 promoter. Glucagon induced LUC activity markedly when the CRE1, but not when the CRE2, sites were in front of the SV40-LUC gene; however, induction of the (CRE1)3SV40-LUC constructs was not modulated by the pO2. Glucagon also induced LUC activity very strongly when the CRE1 and CRE2 sites were combined; induction of the (CRE1)3(CRE2)2SV40-LUC constructs was positively modulated by the pO2. These findings corroborated that sequences of the putative CRE2 site were responsible for the modulation by oxygen of the CRE1-dependent induction by glucagon of PCK1 gene transcription.

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Liu, Zhichao, Yang Yang, Jun Liu, Li Zhu, Hong Yu, Mingjun Zhu, Xi Li, et al. "Circulating tumor DNA (ctDNA) in predicting residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal squamous cell carcinoma (ESCC)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 4044. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.4044.

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4044 Background: For ESCC patients who receive nCRT, high pathological complete response (pCR) rates could be achieved. An active surveillance strategy has been proposed for patients with clinically complete response (cCR) after nCRT. However, clinical assessment may misclassify non-pCR as cCR. This study aimed to investigate the value of ctDNA in predicting tumor response and residual disease after nCRT in ESCC patients. Methods: This was a side study of the prospective, diagnostic pre-SINO trial (NCT03937362). After completion of nCRT, all patients underwent one or two clinical response evaluations (CREs) before planned surgery. The first (CRE‐1) was 4–6 weeks after completion of nCRT. A second examination (CRE‐2) was 10–12 weeks after nCRT for patients without histological evidence of residual tumor at CRE1. Serial ctDNAs were analyzed by ultra-deep unique molecular identifiers -based next-generation sequencing using 168 cancer-related genes at three time points: at baseline (B0), CRE1, CRE2. pCR was defined as ypT0N0M0. cCR was defined as no evidence of residual tumor during CRE1 & CRE2 in endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration cytology. We correlated quantitative ctDNA levels and ctDNA presence with pCR and major locoregional residual disease (MLRD) ( > 10% residual carcinoma or any residual nodal disease). Results: At the time of this initial analysis, 62 consecutive ESCC patients received per-protocol treatments had sufficient sample to test ctDNA. The pCR rate was 32.3% (20/62). ctDNA was detectable in 73.77% at B0, 27.12% at CRE1 and 17.24% at CRE2. Maximum allelic fraction (maxAF) with a > 2-fold decrease post-nCRT (B0-CRE1) was seen in 67% patients with pCR, and 65.2% patients without MLRD. At B0, the high frequency mutated genes detected were TP53 (74%), PIK3CA (13%), CCND1 (11%), FGF19 (11%), FGF3 (11%), and FGF4 (11%). Baseline TP53 mutation status was significantly associated with pathological evaluations. A combining model, which incorporated both CRE1&2 positivity (cCR) and TP53 missense mutation at B0, was developed and demonstrated lower false-negative rate (FNR) in predicting non-pCR (4.9%, 2/41) and MLRD (2.8%, 1/36) compared with clinical assessment only (14.3%, 6/42) and (13.5%, 5/37), respectively. Of note, the FNR of combining clinical assessment and dynamic ctDNA change (continuous drop in maxAF ≥80% [B0-CRE1-CRE2]) was 7.3% (3/41) for non-pCR and MLRD (5.6%, 2/36). Conclusions: ctDNA testing combining with clinical assessment further optimized the tumor response and residual disease evaluations after nCRT for ESCC. ctDNA provides complementary information of response to nCRT and might become useful in an active surveillance strategy for the management of ESCC. Tumor-informed ctDNA analysis designed to track patient-specific somatic variants is ongoing. Clinical trial information: NCT03937362.

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Liu, Zhichao, Yang Yang, Jun Liu, Li Zhu, Hong Yu, Mingjun Zhu, Xi Li, et al. "Circulating tumor DNA (ctDNA) in predicting residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal squamous cell carcinoma (ESCC)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 4044. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.4044.

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4044 Background: For ESCC patients who receive nCRT, high pathological complete response (pCR) rates could be achieved. An active surveillance strategy has been proposed for patients with clinically complete response (cCR) after nCRT. However, clinical assessment may misclassify non-pCR as cCR. This study aimed to investigate the value of ctDNA in predicting tumor response and residual disease after nCRT in ESCC patients. Methods: This was a side study of the prospective, diagnostic pre-SINO trial (NCT03937362). After completion of nCRT, all patients underwent one or two clinical response evaluations (CREs) before planned surgery. The first (CRE‐1) was 4–6 weeks after completion of nCRT. A second examination (CRE‐2) was 10–12 weeks after nCRT for patients without histological evidence of residual tumor at CRE1. Serial ctDNAs were analyzed by ultra-deep unique molecular identifiers -based next-generation sequencing using 168 cancer-related genes at three time points: at baseline (B0), CRE1, CRE2. pCR was defined as ypT0N0M0. cCR was defined as no evidence of residual tumor during CRE1 & CRE2 in endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration cytology. We correlated quantitative ctDNA levels and ctDNA presence with pCR and major locoregional residual disease (MLRD) ( > 10% residual carcinoma or any residual nodal disease). Results: At the time of this initial analysis, 62 consecutive ESCC patients received per-protocol treatments had sufficient sample to test ctDNA. The pCR rate was 32.3% (20/62). ctDNA was detectable in 73.77% at B0, 27.12% at CRE1 and 17.24% at CRE2. Maximum allelic fraction (maxAF) with a > 2-fold decrease post-nCRT (B0-CRE1) was seen in 67% patients with pCR, and 65.2% patients without MLRD. At B0, the high frequency mutated genes detected were TP53 (74%), PIK3CA (13%), CCND1 (11%), FGF19 (11%), FGF3 (11%), and FGF4 (11%). Baseline TP53 mutation status was significantly associated with pathological evaluations. A combining model, which incorporated both CRE1&2 positivity (cCR) and TP53 missense mutation at B0, was developed and demonstrated lower false-negative rate (FNR) in predicting non-pCR (4.9%, 2/41) and MLRD (2.8%, 1/36) compared with clinical assessment only (14.3%, 6/42) and (13.5%, 5/37), respectively. Of note, the FNR of combining clinical assessment and dynamic ctDNA change (continuous drop in maxAF ≥80% [B0-CRE1-CRE2]) was 7.3% (3/41) for non-pCR and MLRD (5.6%, 2/36). Conclusions: ctDNA testing combining with clinical assessment further optimized the tumor response and residual disease evaluations after nCRT for ESCC. ctDNA provides complementary information of response to nCRT and might become useful in an active surveillance strategy for the management of ESCC. Tumor-informed ctDNA analysis designed to track patient-specific somatic variants is ongoing. Clinical trial information: NCT03937362.

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Lemasson, Isabelle, Matthew R. Lewis, Nicholas Polakowski, Patrick Hivin, Marie-Hélène Cavanagh, Sabine Thébault, Benoit Barbeau, Jennifer K. Nyborg, and Jean-Michel Mesnard. "Human T-Cell Leukemia Virus Type 1 (HTLV-1) bZIP Protein Interacts with the Cellular Transcription Factor CREB To Inhibit HTLV-1 Transcription." Journal of Virology 81, no. 4 (December 6, 2006): 1543–53. http://dx.doi.org/10.1128/jvi.00480-06.

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ABSTRACT The complex human T-cell leukemia virus type 1 (HTLV-1) retrovirus encodes several proteins that are unique to the virus within its 3′-end region. Among them, the viral transactivator Tax and posttranscriptional regulator Rex are well characterized, and both positively regulate HTLV-1 viral expression. Less is known about the other regulatory proteins encoded in this region of the provirus, including the recently discovered HBZ protein. HBZ has been shown to negatively regulate basal and Tax-dependent HTLV-1 transcription through its ability to interact with specific basic-leucine zipper (bZIP) proteins. In the present study, we found that HBZ reduces HTLV-1 transcription and virion production. We then characterized the interaction between HBZ and the cellular transcription factor CREB. CREB plays a critical role in Tax-mediated HTLV-1 transcription by forming a complex with Tax that binds to viral cyclic AMP-response elements (CREs) located within the viral promoter. We found that HBZ and CREB interact in vivo and directly in vitro, and this interaction occurs through the bZIP domain of each protein. We also found that CREM-Ia and ATF-1, which share significant homology in their bZIP domains with the bZIP domain of CREB, interact with HBZ-bZIP. The interaction between CREB and HBZ prevents CREB binding to the viral CRE elements in vitro and in vivo, suggesting that the reduction in HTLV-1 transcription by HBZ is partly due to the loss of CREB at the promoter. We also found that HBZ displaces CREB from a cellular CRE, suggesting that HBZ may deregulate CREB-dependent cellular gene expression.

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Denis, C. L., and T. Malvar. "The CCR4 gene from Saccharomyces cerevisiae is required for both nonfermentative and spt-mediated gene expression." Genetics 124, no. 2 (February 1, 1990): 283–91. http://dx.doi.org/10.1093/genetics/124.2.283.

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Abstract Mutations in the yeast CCR4 gene inhibit expression of the glucose-repressible alcohol dehydrogenase (ADH2), as well as other nonfermentative genes, and suppress increased ADH2 expression caused by the cre1 and cre2 alleles. Both the cre1 and ccr4 alleles were shown to affect ADH II enzyme activity by altering the levels of ADH2 mRNA. Mutations in either CRE1 or CRE2 bypassed the inhibition of ADH2 expression caused by delta insertions at the ADH2 promoter which displace the ADH2 activation sequences 336 bp upstream of the TATA element. These cre1 and cre2 effects were suppressible by the ccr4 allele. The cre1 and ccr4 mutations also affected ADH2 expression when all the ADH2 regulatory sequences upstream of the TATA element were deleted. The relationship of the CRE genes to the SPT genes, which when mutated are capable of bypassing the inhibition of HIS4 expression caused by a delta promoter insertion (his4-912 delta allele), was examined. Both the cre1 and cre2 mutations allowed his4-912 delta expression. ccr4 mutations were able to suppress the ability of the cre alleles to increase his4-912 delta expression. CRE2 was shown to be allelic to the SPT6 gene, and CRE1 was found to be allelic to SPT10. We suggest that the CRE genes comprise a general transcriptional control system in yeast that requires the function of the CCR4 gene.

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de Majnik, John, Francis C. Ogbonnaya, Odile Moullet, and Evans S. Lagudah. "The Cre1 and Cre3 Nematode Resistance Genes Are Located at Homeologous Loci in the Wheat Genome." Molecular Plant-Microbe Interactions® 16, no. 12 (December 2003): 1129–34. http://dx.doi.org/10.1094/mpmi.2003.16.12.1129.

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Differential responses in host-nematode pathotype interactions occur in wheat lines carrying different cereal cyst nematode resistance (Cre) genes. Cre1, located on chromosome 2B, confers resistance to most European nematodes and the sole Australian pathotype, while Cre3, present on chromosome 2D, is highly resistant to the Australian patho-type and susceptible to a number of European pathotypes. Genes encoding nucleotide binding site-leucine rich repeat (NBS-LRR) proteins that cosegregate with the Cre3 locus cross hybridize to homologues whose restriction fragment length polymorphism (RFLP) patterns distinguish near-isogenic Cre1 nematode-resistant wheat lines. Genetic mapping showed that the NBS-LRR gene members that distinguished the Cre1 near-isogenic lines were located on chromosome 2BL at a locus, designated Xcsl107, that cosegregates with the Cre1 locus. A haplotype of NBS-LRR genes from the Xcsl107 locus provides a diagnostic marker for the presence of Cre1 nematode resistance in a wide collection of wheat lines and segregating families. Genetic analysis of NBS-LRR haplo-types that cosegregate with Cre1 and Cre3 resistance, together with flanking cDNA markers and other markers from homoeologous group 2 chromosomes, revealed a conserved gene order that suggests Cre1 and Cre3 are homeoloci.

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Collins-Hicok, J., L. Lin, C. Spiro, P. J. Laybourn, R. Tschumper, B. Rapacz, and C. T. McMurray. "Induction of the rat prodynorphin gene through Gs-coupled receptors may involve phosphorylation-dependent derepression and activation." Molecular and Cellular Biology 14, no. 5 (May 1994): 2837–48. http://dx.doi.org/10.1128/mcb.14.5.2837-2848.1994.

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Prodynorphin transcription is activated via Gs-coupled receptors through a cyclic AMP (cAMP)-dependent pathway. Four cAMP response elements (CREs) are present within the rat prodynorphin (RD) control region, and all four CREs appear to function in RD regulation. Three CREs located upstream between -1860 and -1504 are critical for receptor-responsive activity, but their function is distance dependent unless they act together with a fourth CRE found in exon 1. Regulation of RD also appears to involve multiple CRE-binding proteins. Both CRE-binding protein (CREB) and activator protein 1 (AP-1) can regulate RD, but their effects are in opposite directions; CREB represses and AP-1 activates RD. CREB-induced repression and AP-1 activation require distinct elements within the control region, but their binding and functions overlap at CRE-3. While CREB repression is dependent on CRE-3, AP-1 activation (and cAMP induction) of RD requires additional CREs (CRE-1, -2, and -4). CREB repression blocks AP-1 activation in unstimulated cells. However, phosphorylation relieves CREB-induced repression and enhances AP-1 activation. Gs-coupled receptor activation of RD may require phosphorylation-dependent derepression and activation steps.

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Collins-Hicok, J., L. Lin, C. Spiro, P. J. Laybourn, R. Tschumper, B. Rapacz, and C. T. McMurray. "Induction of the rat prodynorphin gene through Gs-coupled receptors may involve phosphorylation-dependent derepression and activation." Molecular and Cellular Biology 14, no. 5 (May 1994): 2837–48. http://dx.doi.org/10.1128/mcb.14.5.2837.

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Prodynorphin transcription is activated via Gs-coupled receptors through a cyclic AMP (cAMP)-dependent pathway. Four cAMP response elements (CREs) are present within the rat prodynorphin (RD) control region, and all four CREs appear to function in RD regulation. Three CREs located upstream between -1860 and -1504 are critical for receptor-responsive activity, but their function is distance dependent unless they act together with a fourth CRE found in exon 1. Regulation of RD also appears to involve multiple CRE-binding proteins. Both CRE-binding protein (CREB) and activator protein 1 (AP-1) can regulate RD, but their effects are in opposite directions; CREB represses and AP-1 activates RD. CREB-induced repression and AP-1 activation require distinct elements within the control region, but their binding and functions overlap at CRE-3. While CREB repression is dependent on CRE-3, AP-1 activation (and cAMP induction) of RD requires additional CREs (CRE-1, -2, and -4). CREB repression blocks AP-1 activation in unstimulated cells. However, phosphorylation relieves CREB-induced repression and enhances AP-1 activation. Gs-coupled receptor activation of RD may require phosphorylation-dependent derepression and activation steps.

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Kim, K., H. S. Hong, K. Oh, J. Y. Lee, S. W. Hong, J. H. Park, S. W. Hwang, et al. "P448 Oral beclomethasone dipropionate as an add-on therapy and response prediction in Korean patients with ulcerative colitis." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i428. http://dx.doi.org/10.1093/ecco-jcc/jjab232.575.

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Abstract Background We aimed to investigate the efficacy of oral beclomethasone dipropionate (BDP) as an add-on therapy to concomitant drugs and to clarify the predictive factors for response to oral BDP in Korean patients with ulcerative colitis (UC). Methods Patients with a stable concomitant drug regimen with exposure to oral BDP (5 mg/day) within 30 days before initiation were included. The partial Mayo score (pMS) was used to evaluate response to oral BDP. Clinical remission (CREM) was defined as a posttreatment pMS ≤1 point. Clinical response (CRES) was defined as an at least 2-points decrease in the posttreatment pMS and an at least 30% decrease from the baseline pMS. Patients without CREM or CRES were considered nonresponders (NRs). Results Of total 100 patients, 37 showed CREM, 19 showed CRES, and 44 were NRs (Table 1). The CREM group included more patients with mild disease activity (75.7% vs. 43.2%, P=0.011) than the NR group. In contrast to NR group, responders including CREM and CRES showed significant improvement of posttreatment ESR and CRP (ESR with P=0.001, CRP with P=0.004, respectively). Moreover, initial rectal bleeding subscore (RBS) was significantly different between CREM and CRES, or NR (both with P<0.001). In multivariate logistic regression analysis, initially mild disease activity was the only predictive factor for CREM (odds ratio, 3.580; 95% confidence interval, 1.342–9.548) (Table 2). Conclusion Oral BDP is efficacious as an add-on therapy in Korean UC patients. In case of acute aggravation, patients with mild disease activity, especially low RBS, may be good candidates for oral BDP.

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Prati, Francesco, Enrico Romagnoli, Marco Valgimigli, Francesco Burzotta, Mauro De Benedictis, Angelo Ramondo, Roxana Mehran, and Pieter R. Stella. "Randomized comparison between 3-month Cre8 DES vs. 1-month Vision/Multilink8 BMS neointimal coverage assessed by OCT evaluation: The DEMONSTRATE study." International Journal of Cardiology 176, no. 3 (October 2014): 904–9. http://dx.doi.org/10.1016/j.ijcard.2014.08.031.

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Fimia, Gian Maria, Dario De Cesare, and Paolo Sassone-Corsi. "A Family of LIM-Only Transcriptional Coactivators: Tissue-Specific Expression and Selective Activation of CREB and CREM." Molecular and Cellular Biology 20, no. 22 (November 15, 2000): 8613–22. http://dx.doi.org/10.1128/mcb.20.22.8613-8622.2000.

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ABSTRACT Transcription factors of the CREB family control the expression of a large number of genes in response to various signaling pathways. Regulation mediated by members of the CREB family has been linked to various physiological functions. Classically, activation by CREB is known to occur upon phosphorylation at an essential regulatory site (Ser133 in CREB) and the subsequent interaction with the ubiquitous coactivator CREB-binding protein (CBP). However, the mechanism by which selectivity is achieved in the identification of target genes, as well as the routes adopted to ensure tissue-specific activation, remains unrecognized. We have recently described the first tissue-specific coactivator of CREB family transcription factors, ACT (activator of CREM in testis). ACT is a LIM-only protein which associates with CREM in male germ cells and provides an activation function which is independent of phosphorylation and CBP. Here we characterize a family of LIM-only proteins which share common structural organization with ACT. These are referred to as four-and-a-half-LIM-domain (FHL) proteins and display tissue-specific and developmentally regulated expression. FHL proteins display different degrees of intrinsic activation potential. They provide powerful activation function to both CREB and CREM when coexpressed either in yeast or in mammalian cells, specific combinations eliciting selective activation. Deletion analysis of the ACT protein shows that the activation function depends on specific arrangements of the LIM domains, which are essential for both transactivation and interaction properties. This study uncovers the existence of a family of tissue-specific coactivators that operate through novel, CBP-independent routes to elicit transcriptional activation by CREB and CREM. The future identification of additional partners of FHL proteins is likely to reveal unappreciated aspects of tissue-specific transcriptional regulation.

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Bleckmann, Susanne C., Julie A. Blendy, Dorothea Rudolph, A. Paula Monaghan, Wolfgang Schmid, and Günther Schütz. "Activating Transcription Factor 1 and CREB Are Important for Cell Survival during Early Mouse Development." Molecular and Cellular Biology 22, no. 6 (March 15, 2002): 1919–25. http://dx.doi.org/10.1128/mcb.22.6.1919-1925.2002.

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ABSTRACT Activating transcription factor 1 (ATF1), CREB, and the cyclic AMP (cAMP) response element modulatory protein (CREM), which constitute a subfamily of the basic leucine zipper transcription factors, activate gene expression by binding as homo- or heterodimers to the cAMP response element in regulatory regions of target genes. To investigate the function of ATF1 in vivo, we inactivated the corresponding gene by homologous recombination. In contrast to CREB-deficient mice, which suffer from perinatal lethality, mice lacking ATF1 do not exhibit any discernible phenotypic abnormalities. Since ATF1 and CREB but not CREM are strongly coexpressed during early mouse development, we generated mice deficient for both CREB and ATF1. ATF1−/− CREB−/− embryos die before implantation due to developmental arrest. ATF1+/− CREB−/− embryos display a phenotype of embryonic lethality around embryonic day 9.5 due to massive apoptosis. These results indicate that CREB and ATF1 act in concert to mediate signals essential for maintaining cell viability during early embryonic development.

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Yin, J. C., J. S. Wallach, E. L. Wilder, J. Klingensmith, D. Dang, N. Perrimon, H. Zhou, T. Tully, and W. G. Quinn. "A Drosophila CREB/CREM homolog encodes multiple isoforms, including a cyclic AMP-dependent protein kinase-responsive transcriptional activator and antagonist." Molecular and Cellular Biology 15, no. 9 (September 1995): 5123–30. http://dx.doi.org/10.1128/mcb.15.9.5123.

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We have characterized a Drosophila gene that is a highly conserved homolog of the mammalian cyclic AMP (cAMP)-responsive transcription factors CREB and CREM. Uniquely among Drosophila genes characterized to date, it codes for a cAMP-responsive transcriptional activator. An alternatively spliced product of the same gene is a specific antagonist of cAMP-inducible transcription. Analysis of the splicing pattern of the gene suggests that the gene may be the predecessor of the mammalian CREB and CREM genes.

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Müller-Tidow, Carsten, Hans-Ulrich Klein, Antje Hascher, Fabienne Isken, Lara Tickenbrock, Nils Thoennissen, Shuchi Agrawal-Singh, et al. "Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia." Blood 116, no. 18 (November 4, 2010): 3564–71. http://dx.doi.org/10.1182/blood-2009-09-240978.

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Abstract Acute myeloid leukemia (AML) is commonly associated with alterations in transcription factors because of altered expression or gene mutations. These changes might induce leukemia-specific patterns of histone modifications. We used chromatin-immunoprecipitation on microarray to analyze histone 3 lysine 9 trimethylation (H3K9me3) patterns in primary AML (n = 108), acute lymphoid leukemia (n = 28), CD34+ cells (n = 21) and white blood cells (n = 15) specimens. Hundreds of promoter regions in AML showed significant alterations in H3K9me3 levels. H3K9me3 deregulation in AML occurred preferentially as a decrease in H3K9me3 levels at core promoter regions. The altered genomic regions showed an overrepresentation of cis-binding sites for ETS and cyclic adenosine monophosphate response elements (CREs) for transcription factors of the CREB/CREM/ATF1 family. The decrease in H3K9me3 levels at CREs was associated with increased CRE-driven promoter activity in AML blasts in vivo. AML-specific H3K9me3 patterns were not associated with known cytogenetic abnormalities. But a signature derived from H3K9me3 patterns predicted event-free survival in AML patients. When the H3K9me3 signature was combined with established clinical prognostic markers, it outperformed prognosis prediction based on clinical parameters alone. These findings demonstrate widespread changes of H3K9me3 levels at gene promoters in AML. Signatures of histone modification patterns are associated with patient prognosis in AML.

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Díaz-Ruiz, Carmen, Rosanna Parlato, Fernando Aguado, Jesús M. Ureña, Ferran Burgaya, Albert Martínez, Maria A. Carmona, et al. "Regulation of neural migration by the CREB/CREM transcription factors and altered Dab1 levels in CREB/CREM mutants." Molecular and Cellular Neuroscience 39, no. 4 (November 2008): 519–28. http://dx.doi.org/10.1016/j.mcn.2008.07.019.

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Powell, Jonathan D., Cara G. Lerner, Gerald R. Ewoldt, and Ronald H. Schwartz. "The −180 Site of the IL-2 Promoter Is the Target of CREB/CREM Binding in T Cell Anergy." Journal of Immunology 163, no. 12 (December 15, 1999): 6631–39. http://dx.doi.org/10.4049/jimmunol.163.12.6631.

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Abstract Anergic T cells display a marked decrease in their ability to produce IL-2 even in the presence of optimal TCR and costimulatory signals. Using IL-2 enhancer/promoter-driven reporter constructs, we have previously identified a region that appears to be a target for cis transcriptional repression in anergy. This region of the promoter, which shares partial homology with a consensus AP-1-binding sequence, is located about −180 bp from the transcriptional start site. In the present study, we demonstrate that cAMP response element-binding protein/cAMP response element modulator (CREB/CREM), activating transcription factor-2/c-Jun, and Jun-Jun/Oct complexes bind to this site. However, the induction of anergy by prolonged stimulation through the TCR led to an increase in binding of only the CREB/CREM complex. Furthermore, the level of binding of this complex appeared to be up-regulated in both resting and restimulated anergic T cells. Finally, an IL-2 promoter-driven reporter construct that contained a mutation that specifically reduced the binding of the CREB/CREM complex displayed a decreased ability to be affected by anergy, while a construct that contained a mutation that decreased the binding of the Jun-Jun/Oct complex was still susceptible to anergy. These findings suggest that the −180 region of the IL-2 promoter is the target of a CREB/CREM transcriptional inhibitor that contributes to the repression of IL-2 production in T cell anergy.

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Clem, Brian F., Elizabeth A. Hudson, and Barbara J. Clark. "Cyclic Adenosine 3′,5′-Monophosphate (cAMP) Enhances cAMP-Responsive Element Binding (CREB) Protein Phosphorylation and Phospho-CREB Interaction with the Mouse Steroidogenic Acute Regulatory Protein Gene Promoter." Endocrinology 146, no. 3 (March 1, 2005): 1348–56. http://dx.doi.org/10.1210/en.2004-0761.

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Steroidogenic acute regulatory protein (StAR) transcription is regulated through cAMP-protein kinase A-dependent mechanisms that involve multiple transcription factors including the cAMP-responsive element binding protein (CREB) family members. Classically, binding of phosphorylated CREB to cis-acting cAMP-responsive elements (5′-TGACGTCA-3′) within target gene promoters leads to recruitment of the coactivator CREB binding protein (CBP). Herein we examined the extent of CREB family member phosphorylation on protein-DNA interactions and CBP recruitment with the StAR promoter. Immunoblot analysis revealed that CREB, cAMP-responsive element modulator (CREM), and activating transcription factor (ATF)-1 are expressed in MA-10 mouse Leydig tumor cells, yet only CREB and ATF-1 are phosphorylated. (Bu)2cAMP treatment of MA-10 cells increased CREB phosphorylation approximately 2.3-fold within 30 min but did not change total nuclear CREB expression levels. Using DNA-affinity chromatography, we now show that CREB and ATF-1, but not CREM, interact with the StAR promoter, and this interaction is dependent on the activator protein-1 (AP-1) cis-acting element within the cAMP-responsive region. In addition, (Bu)2cAMP-treatment increased phosphorylated CREB (P-CREB) association with the StAR promoter but did not influence total CREB interaction. In vivo chromatin immunoprecipitation assays demonstrated CREB binding to the StAR proximal promoter is independent of (Bu)2cAMP-treatment, confirming our in vitro analysis. However, (Bu)2cAMP-treatment increased P-CREB and CBP interaction with the StAR promoter, demonstrating for the first time the physical role of P-CREB:DNA interactions in CBP recruitment to the StAR proximal promoter.

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Ahn, Sohyun, Michelle Olive, Seema Aggarwal, Dmitry Krylov, David D. Ginty, and Charles Vinson. "A Dominant-Negative Inhibitor of CREB Reveals that It Is a General Mediator of Stimulus-Dependent Transcription of c-fos." Molecular and Cellular Biology 18, no. 2 (February 1, 1998): 967–77. http://dx.doi.org/10.1128/mcb.18.2.967.

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ABSTRACT Several studies have characterized the upstream regulatory region of c-fos, and identified cis-acting elements termed the cyclic AMP (cAMP) response elements (CREs) that are critical for c-fos transcription in response to a variety of extracellular stimuli. Although several transcription factors can bind to CREs in vitro, the identity of the transcription factor(s) that activates the c-fos promoter via the CRE in vivo remains unclear. To help identify the trans-acting factors that regulate stimulus-dependent transcription of c-fos via the CREs, dominant-negative (D-N) inhibitor proteins that function by preventing DNA binding of B-ZIP proteins in a dimerization domain-dependent fashion were developed. A D-N inhibitor of CREB, termed A-CREB, was constructed by fusing a designed acidic amphipathic extension onto the N terminus of the CREB leucine zipper domain. The acidic extension of A-CREB interacts with the basic region of CREB forming a coiled-coil extension of the leucine zipper and thus prevents the basic region of wild-type CREB from binding to DNA. Other D-N inhibitors generated in a similar manner with the dimerization domains of Fos, Jun, C/EBP, ATF-2, or VBP did not block CREB DNA binding activity, nor did they inhibit transcriptional activation of a minimal promoter containing a single CRE in PC12 cells. A-CREB inhibited activation of CRE-mediated transcription evoked by three distinct stimuli: forskolin, which increases intracellular cAMP; membrane depolarization, which promotes Ca2+ influx; and nerve growth factor (NGF). A-CREB completely inhibited cAMP-mediated, but only partially inhibited Ca2+- and NGF-mediated, transcription of a reporter gene containing 750 bp of the native c-fos promoter. Moreover, glutamate induction of c-fos expression in primary cortical neurons was dependent on CREB. In contrast, induction of c-fos transcription by UV light was not inhibited by A-CREB. Lastly, A-CREB attenuated NGF induction of morphological differentiation in PC12 cells. These results suggest that CREB or its closely related family members are general mediators of stimulus-dependent transcription of c-fos and are required for at least some of the long-term actions of NGF.

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Journal articles on the topic 'Cre8'

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