Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The yeast transcriptional activator ADR1, which is required for ADH2 and peroxisomal gene expression, contains four separable and partially redundant activation domains (TADs). Mutations in ADA2 or GCN5, encoding components of the ADA coactivator complex involved in histone acetylation, severely reduced LexA-ADR1-TAD activation of a LexA-lacZ reporter gene. Similarly, the ability of the wild-type ADR1 gene to activate an ADH2-driven promoter was compromised in strains deleted for ADA2 or GCN5. In contrast, defects in other general transcription cofactors such as CCR4, CAF1/POP2, and SNF/SWI displayed much less or no effect on LexA-ADR1-TAD activation. Using an in vitro protein binding assay, ADA2 and GCN5 were found to specifically contact individual ADR1 TADs. ADA2 could bind TAD II, and GCN5 physically interacted with all four TADs. Both TADs I and IV were also shown to make specific contacts to the C-terminal segment of TFIIB. In contrast, no significant binding to TBP was observed. TAD IV deletion analysis indicated that its ability to bind GCN5 and TFIIB was directly correlated with its ability to activate transcription in vivo. ADR1 TADs appear to make several contacts, which may help explain both their partial redundancy and their varying requirements at different promoters. The contact to and dependence on GCN5, a histone acetyltransferase, suggests that rearrangement of nucleosomes may be one important means by which ADR1 activates transcription.
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PMID:ADR1 activation domains contact the histone acetyltransferase GCN5 and the core transcriptional factor TFIIB. 894 99

The chromatin structure of the Saccharomyces cerevisiae ADH2 gene is modified during the switch from repressing (high glucose) to derepressing (low glucose) conditions of growth. Loss of protection toward micrococcal nuclease cleavage for the nucleosomes covering the TATA box and the RNA initiation sites (-1 and +1, respectively) is the major modification taking place and is strictly dependent on the presence of the transcriptional activator ADR1. To identify separate functions involved in the transition from a repressed to a transcribing promoter, we have analyzed the ADH2 chromatin organization in various genetic backgrounds. Deletion of the CCR4 gene coding for a general transcription factor impaired ADH2 expression without affecting chromatin remodeling. Growing yeast at 37 degrees C also resulted in chromatin remodeling at the ADH2 locus even under glucose repressing conditions. However, although this temperature-induced remodeling was dependent on the ADR1 protein, no ADH2 mRNA was observed. In addition, inactivating RNA polymerase II (and therefore, elongation) was found to have no effect on the ability to reconfigure nucleosomes. Taken together, these data indicate that chromatin remodeling by itself is insufficient to induce transcription at the ADH2 promoter.
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PMID:Factors affecting Saccharomyces cerevisiae ADH2 chromatin remodeling and transcription. 938 26

Chemokines and chemokine receptors play important roles in migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCR4 in adult T-cell leukemia (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-immortalized T cells. Flow cytometric analysis revealed that ATL and HTLV-1-immortalized T-cell lines consistently expressed CCR4. Inducible expression of HTLV-1 transcriptional activator tax in a human T-cell line Jurkat did not, however, up-regulate CCR4 mRNA. In vitro immortalization of peripheral blood T cells led to preferential outgrowth of CD4(+) T cells expressing CCR4. We further demonstrated highly frequent expression of CCR4 in fresh ATL cells by (1) reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of CCR4 expression in peripheral blood mononuclear cells (PBMCs) from patients with ATL and healthy controls; (2) flow cytometric analysis of CCR4-expressing cells in PBMCs from patients with ATL and healthy controls; (3) CCR4 staining of routine blood smears from patients with ATL; and (4) an efficient migration of fresh ATL cells to the CCR4 ligands, TARC/CCL17 and MDC/CCL22, in chemotaxis assays. Furthermore, we detected strong signals for CCR4, TARC, and MDC in ATL skin lesions by RT-PCR. Collectively, most ATL cases have apparently derived from CD4(+) T cells expressing CCR4. It is now known that circulating CCR4(+) T cells are mostly polarized to Th2 and also contain essentially all skin-seeking memory T cells. Thus, HTLV-1-infected CCR4(+) T cells may have growth advantages by deviating host immune responses to Th2. CCR4 expression may also account for frequent infiltration of ATL into tissues such as skin and lymph nodes.
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PMID:Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. 1186 Dec 61

Adult T-cell leukemia (ATL) is a malignancy of mature T cells that is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1). The frequent manifestation of ATL is infiltration of leukemic cells into various organs. Besides certain cell adhesion molecules and matrix metalloproteineses, chemokine receptors may play important roles in tissue infiltration of ATL. Identification of a unique set of chemokine receptors expressed by ATL would thus provide valuable information about the molecular mechanism of tissue infiltration of ATL. This may also reveal that ATL frequently develops from a certain subset of T cells that express a particular set of chemokine receptors. Since HTLV-1 encodes a potent viral transcriptional activator Tax, which is known to induce various cellular genes, expression of some chemokine receptors may be affected by Tax. This, however, may relate more to HTLV-1-infected T cells, since ATL cells usually do not express Tax. Finally, identification of a unique set of chemokine receptors expressed by ATL may also provide a new therapeutic target. These considerations prompted us to examine the chemokine receptor expression in ATL. We found that in the majority of ATL cases, leukemic cells consistently express CCR4. Since CCR4 is known to be involved in T cell migration into skin, this may in part explain the frequent skin infiltration in ATL. Furthermore, CCR4 is known to be selectively expressed by Th2 and regulatory T cells. Thus, the majority of ATL may predominantly originate from either Th2 or regulatory T cells.
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PMID:Expression of CCR4 in adult T-cell leukemia. 1562

Adult T-cell leukemia (ATL) is a highly aggressive mature CD4+ T-cell malignancy that is etiologically associated with human T-lymphotropic virus Type 1 (HTLV-1). ATL is characterized by frequent infiltration of lymph nodes, spleen, liver, skin and gut. Previously, we and others have shown that the majority of ATL cases are strongly positive for CCR4, which may explain the frequent skin invasion of ATL. Here, we examined whether ATL cells express CCR9, which is involved in T-cell homing to the gastrointestinal tract. Human T cell lines carrying HTLV-1 consistently expressed CCR9 together with the HTLV-1-encoded transcriptional activator Tax. Although ATL cells freshly isolated from peripheral blood hardly expressed CCR9, ATL cells cultured for 1 day consistently expressed CCR9 in parallel with the upregulation of Tax. Induction of Tax by Cd2+ in JPX-9, a subline of Jurkat human T cell line carrying Tax under the control of metallothionein promoter, led to upregulation of CCR9. A luciferase reporter gene under the control of the CCR9 promoter was expressed by cotransfection of an expression vector for Tax or in Cd2+-treated JPX-9 cells. Furthermore, immunohistochemical staining demonstrated that ATL cells infiltrating gastrointestinal tract were frequently positive for CCR9. Collectively, CCR9 is inducible in ATL cells expressing Tax and may play a role in the gastrointestinal involvement of ATL.
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PMID:Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax. 1720 12

Adult T-cell leukemia (ATL) is a malignancy of mature CD4+ T cells that is etiologically associated with the infection of human T-cell leukemia virus type 1 (HTLV-1), an exogenous human retrovirus. Previously, we have shown that leukemic cells of most ATL patients express CCR4, a chemokine receptor known to be selectively expressed by T cell subsets such as Th2 cells, skin-homing memory/effector T cells, and regulatory T cells. Therefore, the expression of CCR4 suggests that ATL cells are mostly derived from one of these T cell subsets. We have also shown that Tax, the HTLV-1-encoded potent transcriptional activator, strongly induces the expression of CCL22, a CCR4 ligand, which promotes the cell-dependent transmission of HTLV-1 from HTLV-1-infected T cells to CCR4+ target T cells by inducing close cell-to-cell interactions. We have also shown that ATL cells aberrantly express the AP-1 family member Fra-2 which, by forming the heterodimer with JunD, potently induces the expression of not only CCR4 but also the genes such as c-Myb, MDM2 and Bcl-6, the well-known proto-oncogenes. Thus, Fra-2 is a novel oncogene of ATL, and CCR4 may be regarded as a useful tumor marker of ATL.
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PMID:[CCR4, HTLV-1 infection, and ATL oncogenesis]. 1937 91