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 human ELL gene on chromosome 19 undergoes frequent translocations with the trithorax-like MLL gene on chromosome 11 in acute myeloid leukemias. Here, ELL was shown to encode a previously uncharacterized elongation factor that can increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by polymerase at multiple sites along the DNA. Functionally, ELL resembles Elongin (SIII), a transcription elongation factor regulated by the product of the von Hippel-Lindau (VHL) tumor suppressor gene. The discovery of a second elongation factor implicated in oncogenesis provides further support for a close connection between the regulation of transcription elongation and cell growth.
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PMID:An RNA polymerase II elongation factor encoded by the human ELL gene. 859 58

The t(6;11)(q27;23) is one of the most common translocations observed in patients with acute myeloid leukemia (AML). The translocation breakpoint involves the MLL gene, which is the human homolog of the Drosophila trithorax gene, at 11q23 and the AF6 gene at 6q27. Reverse transcriptase-polymerase chain reaction (RT-PCR) using an MLL sense primer and an AF6 antisense primer detected the MLL/AF6 fusion cDNA from three leukemia patients with the t(6;11) [two AML and one T-acute lymphoblastic leukemia (ALL)] and one cell line. The fusion point in the AF6 cDNA from these cases is identical, regardless of the leukemia phenotype. The ML-2 cell line, which was established from a patient with AML that developed after complete remission of T-cell lymphoma, has retained an 11q23-24 deletion from the lymphoma stage and has acquired the t(6;11) with development of AML. The ML-2 cells have no normal MLL gene on Southern blot analysis, which indicates that an intact MLL gene is not necessary for survival of leukemic cells.
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PMID:Analysis of the t(6;11)(q27;q23) in leukemia shows a consistent breakpoint in AF6 in three patients and in the ML-2 cell line. 870 46

The human ELL gene on chromosome 19p13.1 undergoes frequent translocations with the trithorax-like MLL gene on chromosome 11q23 in acute myeloid leukemia. Recently, the human ELL gene was shown to encode an RNA polymerase II elongation factor that activates elongation by suppressing transient pausing by polymerase at many sites along the DNA. In this report, we identify and characterize two overlapping ELL functional domains that govern its interaction with RNA polymerase II and the ternary elongation complex. Our findings reveal that, in addition to its elongation activation domain, ELL contains a novel type of RNA polymerase II interaction domain that is capable of negatively regulating polymerase activity in promoter-specific transcription initiation in vitro. Notably, the MLL-ELL translocation results in deletion of a portion of this functional domain, and ELL mutants lacking sequences deleted by the translocation bind RNA polymerase II and are fully active in elongation, but fail to inhibit initiation. Taken together, these results raise the possibility that the MLL-ELL translocation could alter ELL-RNA polymerase II interactions that are not involved in regulation of elongation.
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PMID:Structure and function of RNA polymerase II elongation factor ELL. Identification of two overlapping ELL functional domains that govern its interaction with polymerase and the ternary elongation complex. 926 87

The human ELL gene on chromosome 19 undergoes frequent translocation with the trithorax-like MLL gene on chromosome 11 in acute myeloid leukemia. Recently, it was demonstrated that the product of the human ELL gene encodes an RNA polymerase II elongation factor (Shilatifard, A., Lane, W. S., Jackson, K. W., Conaway, R. C., and Conaway, J. W. (1996) Science 271, 1873-1876). In addition to its elongation regulatory activity, ELL contains a novel type of RNA polymerase II interaction domain that is capable of negatively regulating polymerase activity in promoter-specific transcription in vitro (Shilatifard, A., Haque, D., Conaway, R. C., and Conaway, J. W. (1997) J. Biol. Chem. 272, 22355-22363). Here, we report the identification and purification of a large ELL-containing complex that contains three proteins in addition to ELL and that we have named the Holo-ELL complex. The Holo-ELL complex can increase the catalytic rate of transcription elongation by RNA polymerase II. However, unlike the ELL polypeptide alone, the Holo-ELL complex is not capable of negatively regulating polymerase activity in promoter-specific transcription in vitro. The inability of the Holo-ELL complex to negatively regulate polymerase activity in promoter-specific transcription suggests that one or more of the ELL-associated proteins regulate this activity, possibly through an interaction with the N-terminal domain of the ELL protein, which was shown to be required for the transcriptional inhibitory activity of ELL. Characterization of these ELL interacting proteins should help define the regulation of the biochemical activities of ELL and how loss of this regulation leads to the development of acute myeloid leukemia.
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PMID:Identification and purification of the Holo-ELL complex. Evidence for the presence of ELL-associated proteins that suppress the transcriptional inhibitory activity of ELL. 955 11

ELL was originally identified as a gene that undergoes translocation with the trithorax-like MLL gene in acute myeloid leukemia. Recent studies have shown that the gene product, ELL, functions as an RNA polymerase II elongation factor that increases the rate of transcription by RNA polymerase II by suppressing transient pausing. Using yeast two-hybrid screening with ELL as bait, we isolated the p53 tumor suppressor protein as a specific interactor of ELL. The interaction involves respectively the transcription elongation activation domain of ELL and the C-terminal tail of p53. Through this interaction, ELL inhibits both sequence-specific transactivation and sequence-independent transrepression by p53. Thus, ELL acts as a negative regulator of p53 in transcription. Conversely, p53 inhibits the transcription elongation activity of ELL, suggesting that p53 is capable of regulating general transcription by RNA polymerase II through controlling the ELL activity. Elevated levels of ELL in cells resulted in the inhibition of p53-dependent induction of endogenous p21 and substantially protected cells from p53-mediated apoptosis that is induced by genotoxic stress. Our observations indicate the existence of a mutually inhibitory interaction between p53 and a general transcription elongation factor ELL and raise the possibility that an aberrant interaction between p53 and ELL may play a role in the genesis of leukemias carrying MLL-ELL gene translocations.
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PMID:Physical interaction and functional antagonism between the RNA polymerase II elongation factor ELL and p53. 1035 50

In development, cell identity is maintained by epigenetic functions that prevent changes in cell type-specific transcription programs. Recent insights into gene silencing mechanisms by Polycomb group (PcG) and trithorax group (trxG) proteins reveal that the memory system involves a concerted process of chromatin modification, blocking of RNA polymerase II, and synthesis of noncoding RNA. Remarkably, cell memory is regulated by a balance between repressors and activators that maintains both transcription status and at the same time the possibility of switching to a different state.
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PMID:Polycomb, epigenomes, and control of cell identity. 1262 81

The cellular function of the menin tumor suppressor protein, product of the MEN1 gene mutated in familial multiple endocrine neoplasia type 1, has not been defined. We now show that menin is associated with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L, and other homologs of the yeast Set1 assembly. This menin-associated complex methylates histone H3 on lysine 4. A subset of tumor-derived menin mutants lacks the associated histone methyltransferase activity. In addition, menin is associated with RNA polymerase II whose large subunit carboxyl-terminal domain is phosphorylated on Ser 5. Men1 knockout embryos and cells show decreased expression of the homeobox genes Hoxc6 and Hoxc8. Chromatin immunoprecipitation experiments reveal that menin is bound to the Hoxc8 locus. These results suggest that menin activates the transcription of differentiation-regulating genes by covalent histone modification, and that this activity is related to tumor suppression by MEN1.
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PMID:Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. 1499 27

The Drosophila trithorax group gene brahma (brm) encodes the ATPase subunit of a 2-MDa chromatin-remodeling complex. brm was identified in a screen for transcriptional activators of homeotic genes and subsequently shown to play a global role in transcription by RNA polymerase II. To gain insight into the targeting, function, and regulation of the BRM complex, we screened for mutations that genetically interact with a dominant-negative allele of brm (brm(K804R)). We first screened for dominant mutations that are lethal in combination with a brm(K804R) transgene under control of the brm promoter. In a distinct but related screen, we identified dominant mutations that modify eye defects resulting from expression of brm(K804R) in the eye-antennal imaginal disc. Mutations in three classes of genes were identified in our screens: genes encoding subunits of the BRM complex (brm, moira, and osa), other proteins directly involved in transcription (zerknullt and RpII140), and signaling molecules (Delta and vein). Expression of brm(K804R) in the adult sense organ precursor lineage causes phenotypes similar to those resulting from impaired Delta-Notch signaling. Our results suggest that signaling pathways may regulate the transcription of target genes by regulating the activity of the BRM complex.
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PMID:Genetic screens for enhancers of brahma reveal functional interactions between the BRM chromatin-remodeling complex and the delta-notch signal transduction pathway in Drosophila. 1594 53

Multiple endocrine neoplasia type 1 (MEN-1) is a heritable syndrome typified by tumors in multiple endocrine organs, including the pituitary, parathyroids, and pancreatic islets. MEN-1 is attributable to mutations in the MEN1 tumor-suppressor gene that encodes the menin protein. Recent studies have implicated menin in transcriptional regulation and in covalent histone modification; however, little is known about modifications of the menin protein. Here, we report that menin is subject to phosphorylation on serine residues, including Ser543 and Ser583. Phosphorylation-defective mutants of either or both of these residues retain the associated histone methyltransferase activity of menin, as well as binding to the trithorax complex members Ash2L, Rbbp5, and MLL2 and to RNA polymerase II. Chromatin immunoprecipitation experiments reveal that binding of menin to the Hoxc8 locus is not affected by phosphorylation on Ser543 or Ser583.
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PMID:Phosphorylation of the menin tumor suppressor protein on serine 543 and serine 583. 1705 Jun 72

Recent years have seen unprecedented characterization of mammalian chromatin thanks to advances in chromatin assays, antibody development, and genomics. Genome-wide maps of chromatin state can now be readily acquired using microarrays or next-generation sequencing technologies. These datasets reveal local and long-range chromatin patterns that offer insight into the locations and functions of underlying regulatory elements and genes. These patterns are dynamic across developmental stages and lineages. Global studies of chromatin in embryonic stem cells have led to intriguing hypotheses regarding Polycomb/trithorax and RNA polymerase roles in 'poising' transcription. Chromatin state maps thus provide a rich resource for understanding chromatin at a 'systems level', and a starting point for mechanistic studies aimed at defining epigenetic controls that underlie development.
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PMID:Chromatin state maps: new technologies, new insights. 1833 38


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