Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The general snRNA gene transcription apparatus has been extensively studied. However, the role of coactivators in this process is far from being clearly understood. Here, we have demonstrated that the Drosophila SAGA complex interacts with the PBP complex, the key component of the snRNA gene transcription apparatus, and is present at the promoter regions of the snRNA genes transcribed by both the RNA polymerase II and RNA polymerase III (U6 snRNA). We show that SAGA interacts with the Brf1 transcription factor, which is a part of the RNA polymerase III transcription apparatus and is present at promoters of a number of Pol III-transcribed genes. Mutations inactivating several SAGA subunit genes resulted in reduced snRNA levels in adult flies, indicating that SAGA is indeed the transcriptional coactivator for the snRNA genes. The transcription of the Pol II and Pol III-transcribed U genes was reduced by mutations in all tested SAGA complex subunits. Therefore, the transcription of the Pol II and Pol III-transcribed U genes was reduced by the mutations in the deubiquitinase module, as well as in the acetyltransferase module of the SAGA, indicating that the whole complex is essential for their transcription. Therefore, the SAGA complex activates snRNA genes suggesting its wide involvement in the regulation of gene transcription, and consequently, in the maintenance of cellular homeostasis.
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PMID:The role of SAGA coactivator complex in snRNA transcription. 2999 56

Chemotherapeutic treatment regimens often take advantage of synergistic effects of drug combinations. Anticipating that synergistic effects on the cell biological level likely manifest on the proteome level, the analysis of proteome modulations represents an appropriate strategy to study drug combinations on a molecular level. More specifically, the detection of single proteins exhibiting synergistic abundance changes could be helpful to shed light on key molecules, which contribute in mechanisms facilitating the synergistic interaction and therefore represent potential targets for specific therapeutic approaches. In the reported study we aimed to provide evidence for this assumption and investigated the drug combination of cisplatin and the neddylation inhibitor MLN4924 in HCT-116 cells via cell biological analyses and mass spectrometry-based quantitative proteomics. From 1789 proteins quantified with two unique peptides, activated RNA polymerase II transcriptional coactivator p15 (SUB1) was highlighted as the most synergistically regulated protein using a synergistic scoring approach. Western blotting and analyses of cellular processes associated with this protein (DNA damage, oxidative stress and apoptosis) revealed supporting evidence for the synergistic regulation. Whereas the distinct role of SUB1 in the investigated drug combination needs to be elucidated in future studies, the presented results demonstrated the benefit and feasibility of synergistic scoring of proteome alterations to highlight proteins that likely contribute to the underlying molecular mechanisms of synergistic effects. Data are available via ProteomeXchange with identifier PXD009185.
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PMID:Systematic analysis of synergistic proteome modulations in a drug combination of cisplatin and MLN4924. 3025 9

The class I cyclin family is a well-studied group of structurally conserved proteins that interact with their associated cyclin-dependent kinases (Cdks) to regulate different stages of cell cycle progression depending on their oscillating expression levels. However, the role of class II cyclins, which primarily act as transcription factors and whose expression remains constant throughout the cell cycle, is less well understood. As a classic example of a transcriptional cyclin, cyclin C forms a regulatory sub-complex with its partner kinase Cdk8 and two accessory subunits Med12 and Med13 called the Cdk8-dependent kinase module (CKM). The CKM reversibly associates with the multi-subunit transcriptional coactivator complex, the Mediator, to modulate RNA polymerase II-dependent transcription. Apart from its transcriptional regulatory function, recent research has revealed a novel signaling role for cyclin C at the mitochondria. Upon oxidative stress, cyclin C leaves the nucleus and directly activates the guanosine 5'-triphosphatase (GTPase) Drp1, or Dnm1 in yeast, to induce mitochondrial fragmentation. Importantly, cyclin C-induced mitochondrial fission was found to increase sensitivity of both mammalian and yeast cells to apoptosis. Here, we review and discuss the biology of cyclin C, focusing mainly on its transcriptional and non-transcriptional roles in tumor promotion or suppression.
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PMID:Cyclin C: The Story of a Non-Cycling Cyclin. 3062 Nov 45

The Mediator complex is an essential, multisubunit transcriptional coactivator that is highly conserved in eukaryotes. Mediator interacts with gene-specific transcription factors, the RNA polymerase II transcriptional machinery, as well as several other factors involved in transcription, and acts as an integral hub to regulate various aspects of transcription. Recent studies of the plant Mediator complex have established that it functions in diverse aspects of plant development and fitness. Jasmonate (JA) is an oxylipin-derived plant hormone that regulates plant immunity and development. The basic helix-loop-helix transcription factor MYC2, which is a master regulator of JA signaling, orchestrates genome-wide transcriptional reprogramming of plant cells to coordinate defense- and growth-related processes. Here, we review the function of the plant Mediator complex in regulating JA signaling. We focus on the multifunctional Mediator subunit MED25, which emerges as an integrative hub for the transcriptional regulation of jasmonate signaling.
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PMID:The plant Mediator complex and its role in jasmonate signaling. 3108 85

Shade triggers important adaptive responses such as the shade-avoidance syndrome, which enable plants to respond to the depletion of photosynthetically active light. The basic helix-loop-helix transcription factors PHYTOCHROME INTERACTING FACTORS (PIFs) play a key role in the shade-avoidance syndrome network by regulating the biosynthesis of multiple phytohormones and the expression of cell expansion-related genes. Although much has been learned about the regulation of PIFs in response to shade at the protein level, relatively little is known about the PIF-dependent transcriptional regulation of shade-responsive genes. Mediator is an evolutionarily conserved transcriptional coactivator complex that bridges gene-specific transcription factors with the RNA polymerase II (Pol II) machinery to regulate gene transcription. Here, we report that tomato (Solanum lycopersicum) PIF4 plays an important role in shade-induced hypocotyl elongation by regulating the expression of genes that encode auxin biosynthesis and auxin signaling proteins. During this process, Mediator subunit25 (MED25) physically interacts with PIF4 at the promoter regions of PIF4 target genes and also recruits Pol II to induce gene transcription. Thus, MED25 directly bridges the communication between PIF4 and Pol II general transcriptional machinery to regulate shade-induced hypocotyl elongation. Overall, our results reveal a novel role of MED25 in PIF4-mediated transcriptional regulation under shade.
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PMID:Mediator Subunit MED25 Physically Interacts with PHYTOCHROME INTERACTING FACTOR4 to Regulate Shade-Induced Hypocotyl Elongation in Tomato. 3313 86

Apoptosis antagonizing transcription factor (AATF), an interacting partner of RNA polymerase II is a multifunctional protein that is highly conserved in eukaryotes. In addition to the regulation of gene expression as a transcriptional coactivator, AATF is shown to play a dual role in regulating the cell cycle by displacing histone deacetylases 1 (HDAC1) from the retinoblastoma-E2F transcription factor (Rb-E2F) complex and also from the specificity protein 1 (Sp1) transcription factor responsible for p21 expression, thereby ensuring cell proliferation and growth arrest, respectively, at different checkpoints of the cell cycle. Notably, AATF has emerged as one of the most important modulators of various cellular responses such as proliferation, apoptosis, and survival. Studies have demonstrated that AATF protects cells from multiple stress stimuli such as DNA damage, ER stress, hypoxia, or glucose deprivation by inducing cell cycle arrest, autophagy, or apoptosis inhibition. Furthermore, AATF serves as a critical regulator in various cancers and promotes tumorigenesis by protecting cancer cells from apoptosis induction, favoring cell proliferation, or promoting cell survival by autophagy. Recent studies have demonstrated the key role of AATF in ribosome biosynthesis and have also provided insights into the mechanistic role of AATF, offering impressive cytoprotection in myocardial infarction, neurologic diseases, and nephronophthisis. In this review, we will provide a comprehensive overview of the role of AATF and shed light on its emerging roles underlining the potential use of AATF as a novel biomarker and as an effective therapeutic target.
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PMID:Emerging roles of AATF: Checkpoint signaling and beyond. 3314 63

Liver is the central organ responsible for whole-body metabolism, and its constituent hepatocytes are the major players that carry out liver functions. Although they are highly differentiated and rarely divide, hepatocytes re-enter the cell cycle following hepatic loss due to liver damage or injury. However, the exact molecular mechanisms underlying cell cycle re-entry remain undefined. Gdown1 is an RNA polymerase II (Pol II)-associated protein that has been linked to the function of the Mediator transcriptional coactivator complex. We recently found that Gdown1 ablation in mouse liver leads to down-regulation of highly expressed liver-specific genes and a concomitant cell cycle re-entry associated with the induction of cell cycle-related genes. Unexpectedly, in view of a previously documented inhibitory effect on transcription initiation by Pol II in vitro, we found that Gdown1 is associated with elongating Pol II on the highly expressed genes and that its ablation leads to a reduced Pol II occupancy that correlates with the reduced expression of these genes. Based on these observations, we discuss the in vitro and in vivo functions of Gdown1 and consider mechanisms by which the dysregulated Pol II recruitment associated with Gdown1 loss might induce quiescent cell re-entry into the cell cycle.
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PMID:Regulation of hepatocyte cell cycle re-entry by RNA polymerase II-associated Gdown1. 3323 93


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