scholarly journals Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes

2007 ◽  
Vol 404 (3) ◽  
pp. 459-466 ◽  
Author(s):  
Jianyong Zhang ◽  
Tomonori Hosoya ◽  
Atsushi Maruyama ◽  
Keizo Nishikawa ◽  
Jonathan M. Maher ◽  
...  
Keyword(s):  
Target Genes ◽  
Mutational Analysis ◽  
Binding Protein ◽  
Human Kidney ◽  
Camp Response Element Binding ◽  
Related Factor ◽  
Activation Domains ◽  
Nrf2 Target Gene ◽  
Element Binding Protein

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) contains two transcription activation domains, Neh4 (Nrf2 ECH homology 4) and Neh5, which co-ordinately regulate transactivation of cytoprotective genes. In the present study we aimed to clarify the role of the Neh5 domain in Nrf2-mediated gene regulation. Deletion of the complete Neh5 domain reduces expression of endogenous Nrf2 target genes, such as HO-1 (haem oxygenase 1), NQO1 [NAD(P)H:quinone oxidoreductase 1] and GCLM (glutamate cysteine ligase modulatory subunit), in human kidney epithelial cells. Furthermore, the deletion of Neh5 markedly repressed CBP [CREB (cAMP-response-element-binding protein)-binding protein] and BRG1 (Brahma-related gene 1) from associating with Nrf2, diminishing their co-operative enhancement of HO-1 promoter activity. Mutational analysis of the Neh5 domain revealed a motif that shares significant homology with β-actin and ARP1 (actin-related protein 1). Mutagenesis of this motif selectively decreased HO-1, but not NQO1 and GCLM, expression. Taken together, these results indicate that the Neh5 domain has the ability to regulate Nrf2 target gene transcription, yet the role of the Neh5 domain in transcription varies from gene to gene.

scholarly journals p300/cAMP-response-element-binding-protein ('CREB')-binding protein (CBP) modulates co-operation between myocyte enhancer factor 2A (MEF2A) and thyroid hormone receptor-retinoid X receptor

2003 ◽  
Vol 369 (3) ◽  
pp. 477-484 ◽  
Author(s):  
Antonio De LUCA ◽  
Anna SEVERINO ◽  
Paola De PAOLIS ◽  
Giuliano COTTONE ◽  
Luca De LUCA ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Creb Binding Protein ◽  
Camp Response Element ◽  
Response Element ◽  
Adenovirus E1a ◽  
Element Binding Protein ◽  
Enhancer Factor

Thyroid hormone receptors (TRs) and members of the myocyte enhancer factor 2 (MEF2) family are involved in the regulation of muscle-specific gene expression during myogenesis. Physical interaction between these two factors is required to synergistically activate gene transcription. p300/cAMP-response-element-binding-protein ('CREB')-binding protein (CBP) interacting with transcription factors is able to increase their activity on target gene promoters. We investigated the role of p300 in regulating the TR—MEF2A complex. To this end, we mapped the regions of these proteins involved in physical interactions and we evaluated the expression of a chloramphenicol acetyltransferase (CAT) reporter gene in U2OS cells under control of the α-myosin heavy chain promoter containing the thyroid hormone response element (TRE). Our results suggested a role of p300/CBP in mediating the transactivation effects of the TR—retenoid X receptor (RxR)—MEF2A complex. Our findings showed that the same C-terminal portion of p300 binds the N-terminal domains of both TR and MEF2A, and our in vivo studies demonstrated that TR, MEF2A and p300 form a ternary complex. Moreover, by the use of CAT assays, we demonstrated that adenovirus E1A inhibits activation of transcription by TR—RxR—MEF2A—p300 but not by TR—RxR—MEF2A. Our data suggested that p300 can bind and modulate the activity of TR—RxR—MEF2A at TRE. In addition, it is speculated that p300 might modulate the activity of the TR—RxR—MEF2A complex by recruiting a hypothetical endogenous inhibitor which may act like adenovirus E1A.

scholarly journals Co-activator SRC-1 is dispensable for transcriptional control by STAT3

2009 ◽  
Vol 420 (1) ◽  
pp. 123-132 ◽  
Author(s):  
Helena Cvijic ◽  
Kay Bauer ◽  
Dennis Löffler ◽  
Gabriele Pfeifer ◽  
Conny Blumert ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Target Genes ◽  
Binding Protein ◽  
Myeloma Cell ◽  
Camp Response Element Binding ◽  
Signal Transducer ◽  
Il Interleukin ◽  
Element Binding Protein ◽  
Induced Apoptosis ◽  
Microarray Expression

SRC (steroid receptor co-activator)-1 has been reported to interact with and to be an essential co-activator for several members of the STAT (signal transducer and activator of transcription) family, including STAT3, the major signal transducer of IL (interleukin)-6. We addressed the question of whether SRC-1 is crucial for IL-6- and STAT3-mediated physiological responses such as myeloma cell survival and acute-phase protein induction. In fact, silencing of SRC-1 by RNA interference rapidly induced apoptosis in IL-6-dependent INA-6 human myeloma cells, comparable with what was observed upon silencing of STAT3. Using chromatin immunoprecipitation at STAT3 target regions of various genes, however, we observed constitutive binding of SRC-1 that decreased when INA-6 cells were treated with IL-6. The same held true for STAT3 target genes analysed in HepG2 human hepatocellular carcinoma cells. SRC-1-knockdown studies demonstrated that STAT3-controlled promoters require neither SRC-1 nor the other p160 family members SRC-2 or SRC-3 in HepG2 cells. Furthermore, microarray expression profiling demonstrated that the responsiveness of IL-6 target genes is not affected by SRC-1 silencing. In contrast, co-activators of the CBP [CREB (cAMP-response element-binding protein)-binding protein]/p300 family proved functionally important for the transactivation potential of STAT3 and bound inducibly to STAT3 target regions. This recruitment did not depend on the presence of SRC-1. Altogether, this suggests that functional impairment of STAT3 is not involved in the induction of myeloma cell apoptosis by SRC-1 silencing. We therefore conclude that STAT3 transactivates its target genes by the recruitment of CBP/p300 co-activators and that this process generally does not require the contribution of SRC-1.

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