Regulation of the Amino-Terminal Transcription Activation Domain of Progesterone Receptor by a Cofactor-Induced Protein Folding Mechanism

ABSTRACT We previously identified a small basic leucine zipper (bZIP) protein, Jun dimerization protein 2 (JDP-2), that acts as a coregulator of the N-terminal transcriptional activation domain of progesterone receptor (PR). We show here that JDP-2, through interaction with the DNA binding domain (DBD), induces or stabilizes structure in the N-terminal domain in a manner that correlates with JDP-2 stimulation of transcriptional activity. Circular dichroism spectroscopy experiments showed that JDP-2 interaction caused a significant increase in overall helical content of a two-domain PR polypeptide containing the N-terminal domain and DBD and that the change in structure resides primarily in the N-terminal domain. Thermal melt curves showed that the JDP-2/PR complex is significantly more stable than either protein alone, and partial proteolysis confirmed that JDP-2 interaction alters conformation of the N-terminal domain of PR. Functional analysis of N-terminal domain mutants and receptor chimeras provides evidence that the stimulatory effect of JDP-2 on transcriptional activity of PR is mediated through an interdomain communication between the DBD and the N-terminal domain and that transcriptional activity and functional response to JDP-2 are mediated by multiple elements of the N-terminal domain as opposed to a discrete region.

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Cap ‘n’ collar B cooperates with a small Maf subunit to specify pharyngeal development and suppress deformed homeotic function in the Drosophila head

Development ◽

10.1242/dev.127.18.4023 ◽

2000 ◽

Vol 127 (18) ◽

pp. 4023-4037 ◽

Cited By ~ 3

Author(s):

A. Veraksa ◽

N. McGinnis ◽

X. Li ◽

J. Mohler ◽

W. McGinnis

Keyword(s):

Transcriptional Activation ◽

Protein Function ◽

Leucine Zipper ◽

Suppressive Effect ◽

Basic Leucine Zipper ◽

Transcriptional Activation Domain ◽

Amino Terminal ◽

Culture Cells ◽

Mandibular Segment ◽

Direct Binding

The basic-leucine zipper protein Cap ‘n’ collar B (CncB) suppresses the segmental identity function of the Hox gene Deformed (Dfd) in the mandibular segment of Drosophila embryos. CncB is also required for proper development of intercalary, labral and mandibular structures. In this study, we provide evidence that the CncB-mediated suppression of Dfd requires the Drosophila homolog of the mammalian small Maf proteins, Maf-S, and that the suppression occurs even in the presence of high amounts of Dfd protein. Interestingly, the CncB/Maf-S suppressive effect can be partially reversed by overexpression of Homothorax (Hth), suggesting that Hth and Extradenticle proteins antagonize the effects of CncB/Maf-S on Dfd function in the mandibular segment. In embryos, multimers of simple CncB/Maf-S heterodimer sites are transcriptionally activated in response to CncB, and in tissue culture cells the amino-terminal domain of CncB acts as a strong transcriptional activation domain. There are no good matches to CncB/Maf binding consensus sites in the known elements that are activated in response to Dfd and repressed in a CncB-dependent fashion. This suggests that some of the suppressive effect of CncB/Maf-S proteins on Dfd protein function might be exerted indirectly, while some may be exerted by direct binding to as yet uncharacterized Dfd response elements. We also show that ectopic CncB is sufficient to transform ventral epidermis in the trunk into repetitive arrays of ventral pharynx. We compare the functions of CncB to those of its vertebrate and invertebrate homologs, p45 NF-E2, Nrf and Skn-1 proteins, and suggest that the pharynx selector function of CncB is highly conserved on some branches of the evolutionary tree.

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Fos and jun cooperate in transcriptional regulation via heterologous activation domains.

Molecular and Cellular Biology ◽

10.1128/mcb.10.10.5532 ◽

1990 ◽

Vol 10 (10) ◽

pp. 5532-5535 ◽

Cited By ~ 45

Author(s):

C Abate ◽

D Luk ◽

E Gagne ◽

R G Roeder ◽

T Curran

Keyword(s):

Gene Expression ◽

Transcriptional Activation ◽

Transcriptional Activity ◽

Regulation Of Gene Expression ◽

Negative Influence ◽

Activation Domain ◽

Activation Domains ◽

Transcriptional Activation Domain ◽

Transcriptional Stimulation

The products of c-fos and c-jun (Fos and Jun) function in gene regulation by interacting with the AP-1 binding site. Here we have examined the contribution of Fos and Jun toward transcriptional activity by using Fos and Jun polypeptides purified from Escherichia coli. Fos contained a transcriptional activation domain as well as a region which exerted a negative influence on transcriptional activity in vitro. Moreover, distinct activation domains in both Fos and Jun functioned cooperatively in transcriptional stimulation. Thus, regulation of gene expression by Fos and Jun results from an integration of several functional domains in a bimolecular complex.

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The proto-oncogene HLF and the related basic leucine zipper protein TEF display highly similar DNA-binding and transcriptional regulatory properties

Blood ◽

10.1182/blood.v87.11.4607.bloodjournal87114607 ◽

1996 ◽

Vol 87 (11) ◽

pp. 4607-4617 ◽

Cited By ~ 21

Author(s):

SP Hunger ◽

S Li ◽

MZ Fall ◽

L Naumovski ◽

ML Cleary

Keyword(s):

Amino Acid ◽

Dna Binding ◽

Transcriptional Activation ◽

Leucine Zipper ◽

Lymphoblastic Leukemia ◽

Consensus Sequence ◽

Basic Leucine Zipper ◽

Amino Terminal ◽

Transcriptional Regulatory ◽

Regulatory Properties

Genes encoding transcription factors are frequently altered by chromosomal translocations in acute lymphoblastic leukemia (ALL), suggesting that aberrant transcriptional regulation plays a prominent role in leukemogenesis. E2A-hepatic leukemia factor (HLF), a chimeric transcription factor created by the t(17;19), consists of the amino terminal portion of E2A proteins, including two experimentally defined transcriptional activation domains (TADs), fused to the HLF DNA binding and protein dimerization basic leucine zipper (bZIP) domain. To understand the mechanisms by which E2A-HLF induces leukemia and the crucial functions contributed by each constituent of the chimera, it is essential to define the normal transcriptional regulatory properties of HLF and related bZIP proteins. To address these questions, we cloned the human homologue of TEF/VBP, a bZIP protein closely related to HLF. Using a binding site selection assay, we found that TEF bound preferentially to the consensus sequence 5′-GTTACGTAAT-3′, which is identical to the previously determined HLF recognition site. TEF and HLF activated transcription of consensus site-containing reporter genes in several different cell types with similar potencies. Using GAL4 chimeric proteins, a TAD was mapped to a discrete approximate 40 amino acid region of TEF and HLF within which they share 72% amino acid identity and 85% similarity. The TEF/HLF activation domain (THAD) has a predicted helical secondary structure, but shares no sequence homology with previously reported TADs. The THAD contained most, if not all, of the transcriptional activation properties present in both TEF and HLF and its deletion completely abrogated transcriptional activity of TEF and HLF in both mammalian cells and yeast. Thus, TEF and HLF share indistinguishable DNA-binding and transcriptional regulatory properties, whose alteration in leukemia may be pathogenetically important.

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Fos and jun cooperate in transcriptional regulation via heterologous activation domains

Molecular and Cellular Biology ◽

10.1128/mcb.10.10.5532-5535.1990 ◽

1990 ◽

Vol 10 (10) ◽

pp. 5532-5535

Author(s):

C Abate ◽

D Luk ◽

E Gagne ◽

R G Roeder ◽

T Curran

Keyword(s):

Gene Expression ◽

Transcriptional Activation ◽

Transcriptional Activity ◽

Regulation Of Gene Expression ◽

Negative Influence ◽

Activation Domain ◽

Activation Domains ◽

Transcriptional Activation Domain ◽

Transcriptional Stimulation

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Multicentric Carpotarsal Osteolysis Is Caused by Mutations Clustering in the Amino-Terminal Transcriptional Activation Domain of MAFB

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2012.03.019 ◽

2014 ◽

Vol 94 (4) ◽

pp. 643 ◽

Cited By ~ 1

Author(s):

Andreas Zankl ◽

Emma L. Duncan ◽

Paul J. Leo ◽

Graeme R. Clark ◽

Evgeny A. Glazov ◽

...

Keyword(s):

Transcriptional Activation ◽

Activation Domain ◽

Transcriptional Activation Domain ◽

Amino Terminal

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Multicentric Carpotarsal Osteolysis Is Caused by Mutations Clustering in the Amino-Terminal Transcriptional Activation Domain of MAFB

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2012.01.003 ◽

2012 ◽

Vol 90 (3) ◽

pp. 494-501 ◽

Cited By ~ 55

Author(s):

Andreas Zankl ◽

Emma L. Duncan ◽

Paul J. Leo ◽

Graeme R. Clark ◽

Evgeny A. Glazov ◽

...

Keyword(s):

Transcriptional Activation ◽

Activation Domain ◽

Transcriptional Activation Domain ◽

Amino Terminal

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Inhibition of BATF/JUN transcriptional activity protects against osteoarthritic cartilage destruction

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-208953 ◽

2016 ◽

Vol 76 (2) ◽

pp. 427-434 ◽

Cited By ~ 19

Author(s):

Jinseol Rhee ◽

Seo-Hee Park ◽

Seul-Ki Kim ◽

Jin-Hong Kim ◽

Chul-Won Ha ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Activation ◽

Transcriptional Activity ◽

Leucine Zipper ◽

Cartilage Destruction ◽

Osteoarthritic Cartilage ◽

Basic Leucine Zipper ◽

Degrading Enzymes ◽

Matrix Degrading Enzymes ◽

Jun B

ObjectiveThe basic leucine zipper transcription factor, ATF-like (BATF), a member of the Activator protein-1 family, promotes transcriptional activation or repression, depending on the interacting partners (JUN-B or C-JUN). Here, we investigated whether the BATF/JUN complex exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of osteoarthritis (OA).MethodsPrimary cultured mouse chondrocytes were treated with proinflammatory cytokines (interleukin-1β, IL-6 or tumour necrosis factor-α) or infected with adenoviruses carrying the Batf gene (Ad-Batf). Expression of BATF and JUN was examined in human and mouse experimental OA cartilage samples. Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of Ad-Batf. The chromatin immunoprecipitation assay was used to examine the binding of BATF and JUN to the promoter regions of candidate genes.ResultsOverexpression of BATF, which forms a heterodimeric complex with JUN-B and C-JUN, induced upregulation of matrix-degrading enzymes and downregulation of cartilage matrix molecules in chondrocytes. BATF expression in mouse joint tissues promoted OA cartilage destruction, and conversely, knockout of Batf in mice suppressed experimental OA. Pharmacological inhibition of BATF/JUN transcriptional activity reduced the expression of matrix-degrading enzymes and protected against experimental OA in mice.ConclusionsBATF/JUN-B and BATF/C-JUN complexes play important roles in OA cartilage destruction through regulating anabolic and catabolic gene expression in chondrocytes. Our findings collectively support the utility of BATF as a therapeutic target for OA.

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The N-terminal domain is a transcriptional activation domain required for Nanog to maintain ES cell self-renewal

Chinese Science Bulletin ◽

10.1007/s11434-009-0530-7 ◽

2009 ◽

Vol 54 (18) ◽

pp. 3271-3277 ◽

Cited By ~ 2

Author(s):

YunQian Guo ◽

Juan Zhang ◽

Li Ye ◽

Mo Chen ◽

Dong Yao ◽

...

Keyword(s):

Transcriptional Activation ◽

Es Cell ◽

Activation Domain ◽

Self Renewal ◽

Transcriptional Activation Domain ◽

Terminal Domain

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Functional and Placental Expression Analysis of the Human NRF3 Transcription Factor

Molecular Endocrinology ◽

10.1210/me.2003-0379 ◽

2005 ◽

Vol 19 (1) ◽

pp. 125-137 ◽

Cited By ~ 28

Author(s):

Benoı̂t Chénais ◽

Anna Derjuga ◽

Wael Massrieh ◽

Kristy Red-Horse ◽

Valerie Bellingard ◽

...

Keyword(s):

Transcriptional Activation ◽

Leucine Zipper ◽

Related Factor ◽

Nuclear Factor ◽

Basic Leucine Zipper ◽

Transcriptional Activation Domain ◽

Functional Studies ◽

Recognition Element ◽

Protein Levels

Abstract Members of the Maf protooncogene and cap’n’ collar families of basic-leucine zipper transcription factors play important roles in development, differentiation, oncogenesis, and stress signaling. In this study, we performed an in vivo protein-protein interaction screen to search for novel partners of the small Maf proteins. Using full-length human MAFG protein as bait, we identified the human basic-leucine zipper protein NRF3 [NF-E2 (nuclear factor erythroid 2)-related factor 3] as an interaction partner. Transfection studies confirmed that NRF3 is able to dimerize with MAFG. The resulting NRF3/MAFG heterodimer recognizes nuclear factor-erythroid 2/Maf recognition element-type DNA-binding motifs. Functional analysis revealed the presence of a strong transcriptional activation domain in the center region of the NRF3 protein. We found that NRF3 transcripts are present in placental chorionic villi from at least week 12 of gestation on through term. In particular, NRF3 is highly expressed in primary placental cytotrophoblasts, but not in placental fibroblasts. The human choriocarcinoma cell lines BeWo and JAR, derived from trophoblastic tumors of the placenta, also strongly express NRF3 transcripts. We generated a NRF3-specific antiserum and identified NRF3 protein in placental choriocarcinoma cells. Furthermore, we showed that NRF3 transcript and protein levels are induced by TNF-α in JAR cells. Our functional studies suggest that human NRF3 is a potent transcriptional activator. Finally, our expression and induction analyses hint at a possible role of Nrf3 in placental gene expression and development.

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Interaction of ATF6 and serum response factor.

Molecular and Cellular Biology ◽

10.1128/mcb.17.9.4957 ◽

1997 ◽

Vol 17 (9) ◽

pp. 4957-4966 ◽

Cited By ~ 124

Author(s):

C Zhu ◽

F E Johansen ◽

R Prywes

Keyword(s):

Reporter Gene ◽

Transcriptional Activation ◽

Leucine Zipper ◽

Serum Response Factor ◽

Response Factor ◽

Basic Leucine Zipper ◽

Transcriptional Activation Domain ◽

Activation Of Transcription ◽

Serum Response

Serum response factor (SRF) is a transcription factor which binds to the serum response element (SRE) in the c-fos promoter. It is required for regulated expression of the c-fos gene as well as other immediate-early genes and some tissue-specific genes. To better understand the regulation of SRF, we used a yeast interaction assay to screen a human HeLa cell cDNA library for SRF-interacting proteins. ATF6, a basic-leucine zipper protein, was isolated by binding to SRF and in particular to its transcriptional activation domain. The binding of ATF6 to SRF was also detected in vitro. An ATF6-VP16 chimera activated expression of an SRE reporter gene in HeLa cells, suggesting that ATF6 can interact with endogenous SRF. More strikingly, an antisense ATF6 construct reduced serum induction of a c-fos reporter gene, suggesting that ATF6 is involved in activation of transcription by SRF. ATF6 was previously partially cloned as a member of the ATF family. The complete cDNA of ATF6 was isolated, and its expression pattern was described.

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