scholarly journals S100A8/S100A9 cytokine acts as a transcriptional coactivator during breast cellular transformation

2021 ◽  
Vol 7 (1) ◽  
pp. eabe5357
Author(s):  
Ruisheng Song ◽  
Kevin Struhl
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Cellular Transformation ◽  
Extracellular Proteins ◽  
Sequence Motifs ◽  
Transcriptional Coactivator ◽  
Specific Expression ◽  
Calcium Dependent ◽  
Nuclear Extracts ◽  
Dna Sequence Motifs

Cytokines are extracellular proteins that convey messages between cells by interacting with cognate receptors at the cell surface and triggering signaling pathways that alter gene expression and other phenotypes in an autocrine or paracrine manner. Here, we show that the calcium-dependent cytokines S100A8 and S100A9 are recruited to numerous promoters and enhancers in a model of breast cellular transformation. This recruitment is associated with multiple DNA sequence motifs recognized by DNA binding transcription factors that are linked to transcriptional activation and are important for transformation. The cytokines interact with these transcription factors in nuclear extracts, and they activate transcription when artificially recruited to a target promoter. Nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and leads to enhanced breast transformation phenotype. These results suggest that, in addition to its classical cytokine function, S100A8/A9 can act as a transcriptional coactivator.

scholarly journals Adenovirus E1A specifically blocks SWI/SNF-dependent transcriptional activation.

1996 ◽  
Vol 16 (10) ◽  
pp. 5737-5743 ◽  
Author(s):  
M E Miller ◽  
B R Cairns ◽  
R S Levinson ◽  
K R Yamamoto ◽  
D A Engel ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Cellular Transformation ◽  
Transcriptional Coactivator ◽  
Gene Encoding ◽  
Adenovirus E1a ◽  
Transcriptional Regulatory ◽  
Genes Encoding ◽  
Regulatory Complex ◽  
Activation Pathways ◽  
Coactivator P300

Expression of the adenovirus E1A243 oncoprotein in Saccharomyces cerevisiae produces a slow-growth phenotype with accumulation of cells in the G1 phase of the cell cycle. This effect is due to the N-terminal and CR1 domains of E1A243, which in rodent cells are involved in triggering cellular transformation and also in binding to the cellular transcriptional coactivator p300. A genetic screen was undertaken to identify genes required for the function of E1A243 in S. cerevisiae. This screen identified SNF12, a gene encoding the 73-kDa subunit of the SWI/SNF transcriptional regulatory complex. Mutation of genes encoding known members of the SWI/SNF complex also led to loss of E1A function, suggesting that the SWI/SNF complex is a target of E1A243. Moreover, expression of E1A in wild-type cells specifically blocked transcriptional activation of the INO1 and SUC2 genes, whose activation pathways are distinct but have a common requirement for the SWI/SNF complex. These data demonstrate a specific functional interaction between E1A and the SWI/SNF complex and suggest that a similar interaction takes place in rodent and human cells.

scholarly journals A novel cis-acting element controlling the rat CYP2D5 gene and requiring cooperativity between C/EBP beta and an Sp1 factor.

1994 ◽  
Vol 14 (2) ◽  
pp. 1383-1394 ◽  
Author(s):  
Y H Lee ◽  
M Yano ◽  
S Y Liu ◽  
E Matsunaga ◽  
P F Johnson ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Ternary Complex ◽  
Sequence Similarity ◽  
Consensus Sequence ◽  
Regulatory Region ◽  
Mrna Levels ◽  
Binding Studies ◽  
Mobility Shift ◽  
Specific Expression ◽  
Nuclear Extracts

The rat CYP2D5 gene encodes a cytochrome P450 and is expressed in liver cells. Its expression commences a few days after birth, and maximal mRNA levels are achieved when animals reach puberty. Transfection and DNA binding studies were performed to investigate the mechanism controlling developmentally programmed, liver-specific expression of CYP2D5. Transfection studies using a series of CYP2D5 upstream DNA chloramphenicol acetyltransferase gene fusion constructs identified a segment of DNA between nucleotides -55 and -156 that conferred transcriptional activity in HepG2 cells. Activity was markedly increased by cotransfection with a vector expressing C/EBP beta but was unaffected by vectors producing other liver-enriched transcription factors (C/EBP alpha, HNF-1 alpha, and DBP). DNase I footprinting revealed a region protected by both HepG2 and liver cell nuclear extracts between nucleotides -83 and -112. This region displayed some sequence similarity to the Sp1 consensus sequence and was able to bind the Sp1 protein, as assessed by a gel mobility shift assay. The role of Sp1 in CYP2D5 transcription was confirmed by trans activation of the 2D5-CAT construct in Drosophila melanogaster cells by using an Sp1 expression vector. C/EBP beta alone was unable to directly bind the -83 to -112 region of the promoter but was able to produce a ternary complex when combined with HepG2 nuclear extracts or recombinant human Sp1. C/EBP alpha was unable to substitute for C/EBP beta in forming this ternary complex. A poor C/EBP binding site is present adjacent to the Sp1 site, and mutagenesis of this site abolished formation of the ternary complex with the CYP2D5 regulatory region. These result establish that two transcription factors can work in conjunction, possibly by protein-protein interaction, to activate the CYP2D5 gene.

A 5′ Regulatory Sequence Containing Two Ets Motifs Controls the Expression of the Wiskott-Aldrich Syndrome Protein (WASP) Gene in Human Hematopoietic Cells

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4554-4560 ◽  
Author(s):  
A. Petrella ◽  
I. Doti ◽  
V. Agosti ◽  
P. Carandente Giarrusso ◽  
D. Vitale ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Jurkat Cells ◽  
Regulatory Sequence ◽  
Regulatory Sequences ◽  
Specific Expression ◽  
Wiskott Aldrich Syndrome ◽  
Nuclear Extracts ◽  
Ets Family ◽  
Wasp Gene ◽  
Syndrome Protein

The recently-identified Wiskott-Aldrich syndrome protein gene (WASP) is responsible for the Wiskott-Aldrich X-linked immunodeficiency as well as for isolated X-linked thrombocytopenia (XLT). To characterize the regulatory sequences of the WASP gene, we have isolated, sequenced and functionally analyzed a 1.6-Kb DNA fragment upstream of the WASP coding sequence. Transfection experiments showed that this fragment is capable of directing efficient expression of the reporter chloramphenicol acetyltransferase (CAT) gene in all human hematopoietic cell lines tested. Progressive 5′ deletions showed that the minimal sequence required for hematopoietic-specific expression consists of 137 bp upstream of the transcription start site. This contains potential binding sites for several hematopoietic transcription factors and, in particular, two Ets-1 consensus that proved able to specifically bind to proteins present in nuclear extracts of Jurkat cells. Overexpression of Ets-1 in HeLa resulted in transactivation of the CAT reporter gene under the control of WASP regulatory sequences. Disruption of the Ets-binding sequences by side-directed mutagenesis abolished CAT expression in Jurkat cells, indicating that transcription factors of the Ets family play a key role in the control of WASP transcription.

scholarly journals A Family of LIM-Only Transcriptional Coactivators: Tissue-Specific Expression and Selective Activation of CREB and CREM

2000 ◽  
Vol 20 (22) ◽  
pp. 8613-8622 ◽  
Author(s):  
Gian Maria Fimia ◽  
Dario De Cesare ◽  
Paolo Sassone-Corsi
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Target Genes ◽  
Activation Function ◽  
Creb Binding Protein ◽  
Selective Activation ◽  
Specific Expression ◽  
Tissue Specific ◽  
Family Control

ABSTRACT Transcription factors of the CREB family control the expression of a large number of genes in response to various signaling pathways. Regulation mediated by members of the CREB family has been linked to various physiological functions. Classically, activation by CREB is known to occur upon phosphorylation at an essential regulatory site (Ser133 in CREB) and the subsequent interaction with the ubiquitous coactivator CREB-binding protein (CBP). However, the mechanism by which selectivity is achieved in the identification of target genes, as well as the routes adopted to ensure tissue-specific activation, remains unrecognized. We have recently described the first tissue-specific coactivator of CREB family transcription factors, ACT (activator of CREM in testis). ACT is a LIM-only protein which associates with CREM in male germ cells and provides an activation function which is independent of phosphorylation and CBP. Here we characterize a family of LIM-only proteins which share common structural organization with ACT. These are referred to as four-and-a-half-LIM-domain (FHL) proteins and display tissue-specific and developmentally regulated expression. FHL proteins display different degrees of intrinsic activation potential. They provide powerful activation function to both CREB and CREM when coexpressed either in yeast or in mammalian cells, specific combinations eliciting selective activation. Deletion analysis of the ACT protein shows that the activation function depends on specific arrangements of the LIM domains, which are essential for both transactivation and interaction properties. This study uncovers the existence of a family of tissue-specific coactivators that operate through novel, CBP-independent routes to elicit transcriptional activation by CREB and CREM. The future identification of additional partners of FHL proteins is likely to reveal unappreciated aspects of tissue-specific transcriptional regulation.

scholarly journals Identifying DNA Sequence Motifs of Pdx-1 and NeuroD1 Transcription Factors

10.29007/sfxr ◽  
2019 ◽  
Author(s):  
Hassan Aldarwish ◽  
David Keller ◽  
Elena Harris
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Beta Cells ◽  
Type I Diabetes ◽  
Motif Finding ◽  
Type I ◽  
Sequence Motifs ◽  
Regulate Gene Expression ◽  
Treatment Of Diabetes ◽  
Dna Sequence Motifs

Diabetes is a disease reported to be the 8th leading cause of death across the world. Nearly 38 million people worldwide have Type I diabetes caused by a dysfunction of beta cells that impairs insulin production. A better understanding of mechanisms related to gene expression in beta cells might help in the development of novel strategies for the effective treatment of diabetes. Two known transcription factors, Pdx-1 and NeuroD1, are shown to regulate gene expression in beta cells. Recently gene targets that are regulated by both Pdx-1 and NeuroD1 have been identified experimentally [7]. However, the motifs for this set of genes have not been found yet. Here we undertake the task of finding statistically overrepresented motifs in genes regulated by Pdx-1 and NeuroD1. The challenge of this project is to identify statistically significant pairs of motifs: one motif of each pair is for Pdx-1 and the other for NeuroD1. Commonly known motif-finding methods are usually restricted to finding a set of potential candidates, each of which is a single motif.

scholarly journals Involvement of an AP-1 complex in zone-specific expression of the CYP11B1 gene in the rat adrenal cortex.

1995 ◽  
Vol 15 (11) ◽  
pp. 6003-6012 ◽  
Author(s):  
K Mukai ◽  
F Mitani ◽  
H Shimada ◽  
Y Ishimura
Keyword(s):  
Transcription Factor ◽  
Adrenal Cortex ◽  
Transcriptional Activation ◽  
Expression System ◽  
Regulatory Region ◽  
Gene Promoter ◽  
Suppressive Effect ◽  
Zona Fasciculata ◽  
Specific Expression ◽  
Nuclear Extracts

The CYP11B1 gene, which encodes steroid 11 beta-monooxygenase, which is responsible for the synthesis of cortisol and corticosterone, the major glucocorticoids in mammals, is expressed specifically in the zona fasciculata of the adrenal cortex. We have analyzed the promoter region of the rat CYP11B1 gene by using a transient-expression system with adrenocortical Y1 cells and have identified a positive regulatory region. The region contained two adjacent sites for the binding of Y1-cell nuclear proteins: the binding site for an AP-1 transcription factor composed of JunD and a Fos-related protein, and the site for Ad4-binding protein (Ad4BP). The binding of the AP-1 factor to the regulatory region had a suppressive effect on that of Ad4BP in the nuclear extracts. Mutational analyses revealed that the transcriptional activation of the CYP11B1 gene promoter in Y1 cells was attributable to the AP-1 site but not to the Ad4 site. Subsequently, nuclear extracts of the zona fasciculata cells from the rat adrenal cortex were found to contain both AP-1 factor and Ad4BP, whose binding properties to the regulatory region were almost identical to those of the two factors in the Y1-cell nuclear extracts. Moreover, immunohistochemical analyses of rat adrenal cortices showed that the AP-1 factor was present in the nuclei of CYP11B1-expressing cells in the zona fasciculata but not in the nuclei of cells in the other zones. From these results, we propose that the AP-1 transcription factor found in this study plays an important role in the zone-specific expression of the CYP11B1 gene in rat adrenal cortex.

scholarly journals YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation

2021 ◽  
Author(s):  
Lizhi He ◽  
Henry Pratt ◽  
Fengxiang Wei ◽  
Mingshi Gao ◽  
Zhiping Weng ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Cellular Transformation ◽  
Sequence Motifs ◽  
Breast Cancer Patients ◽  
Key Factors ◽  
Epigenetic Switch ◽  
Target Sites ◽  
Negative Form

ABSTRACTThe YAP and TAZ paralogues are transcriptional co-activators recruited to target sites, primarily by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB and STAT3, key factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, co-occupy many target sites in vivo via AP-1 and (to a lesser extent) STAT3 sequence motifs, and stimulate transcriptional activation by AP-1 proteins. A few target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes. YAP/TAZ, JUNB, and STAT3 directly regulate a common set of target genes that overlap, but are distinct from, those regulated by YAP/TAZ and TEADs. The set of genes regulated by YAP/TAZ, STAT3, and JUNB is associated with poor survival in breast cancer patients with the triple-negative form of the disease.

A 5′ Regulatory Sequence Containing Two Ets Motifs Controls the Expression of the Wiskott-Aldrich Syndrome Protein (WASP) Gene in Human Hematopoietic Cells

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4554-4560 ◽  
Author(s):  
A. Petrella ◽  
I. Doti ◽  
V. Agosti ◽  
P. Carandente Giarrusso ◽  
D. Vitale ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Jurkat Cells ◽  
Regulatory Sequence ◽  
Regulatory Sequences ◽  
Specific Expression ◽  
Wiskott Aldrich Syndrome ◽  
Nuclear Extracts ◽  
Ets Family ◽  
Wasp Gene ◽  
Syndrome Protein

Abstract The recently-identified Wiskott-Aldrich syndrome protein gene (WASP) is responsible for the Wiskott-Aldrich X-linked immunodeficiency as well as for isolated X-linked thrombocytopenia (XLT). To characterize the regulatory sequences of the WASP gene, we have isolated, sequenced and functionally analyzed a 1.6-Kb DNA fragment upstream of the WASP coding sequence. Transfection experiments showed that this fragment is capable of directing efficient expression of the reporter chloramphenicol acetyltransferase (CAT) gene in all human hematopoietic cell lines tested. Progressive 5′ deletions showed that the minimal sequence required for hematopoietic-specific expression consists of 137 bp upstream of the transcription start site. This contains potential binding sites for several hematopoietic transcription factors and, in particular, two Ets-1 consensus that proved able to specifically bind to proteins present in nuclear extracts of Jurkat cells. Overexpression of Ets-1 in HeLa resulted in transactivation of the CAT reporter gene under the control of WASP regulatory sequences. Disruption of the Ets-binding sequences by side-directed mutagenesis abolished CAT expression in Jurkat cells, indicating that transcription factors of the Ets family play a key role in the control of WASP transcription.

scholarly journals YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lizhi He ◽  
Henry Pratt ◽  
Mingshi Gao ◽  
Fengxiang Wei ◽  
Zhiping Weng ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Triple Negative ◽  
Cellular Transformation ◽  
Sequence Motifs ◽  
Overlapping Genes ◽  
Breast Cancer Patients ◽  
Poor Survival ◽  
Epigenetic Switch ◽  
Target Sites ◽  
Negative Form

The YAP and TAZ paralogs are transcriptional co-activators recruited to target sites by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB (a member of the AP-1 family) and STAT3, key transcription factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, and they stimulate transcriptional activation by AP-1 proteins. JUNB, STAT3, and TEAD co-localize at virtually all YAP/TAZ target sites, yet many target sites only contain individual AP-1, TEAD, or STAT3 motifs. This observation and differences in relative crosslinking efficiencies of JUNB, TEAD, and STAT3 at YAP/TAZ target sites suggest that YAP/TAZ is recruited by different forms of an AP-1/STAT3/TEAD complex depending on the recruiting motif. The different classes of YAP/TAZ target sites are associated with largely non-overlapping genes with distinct functions. A small minority of target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes from shared YAP/TAZ target sites. Genes containing either the AP-1 or TEAD class of YAP/TAZ sites are associated with poor survival of breast cancer patients with the triple-negative form of the disease.

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