When ETS transcription factors meet their partners
ABSTRACT Ets proteins are a family of transcription factors that regulate the expression of a myriad of genes in a variety of tissues and cell types. This functional versatility emerges from their interactions with other structurally unrelated transcription factors. Indeed, combinatorial control is a characteristic property of Ets family members, involving interactions between Ets and other key transcriptional factors such as AP1, SRF, and Pax family members. Intriguingly, recent molecular modeling and crystallographic data suggest that not only the ETS DNA-binding domain, but also the DNA recognition helix alpha3, are often directly required for Ets partner's selection. Indeed, while most DNA-binding proteins appear to exploit differences within their DNA recognition helices for sites selection, the Ets proteins exploit differences in their surfaces that interact with other transcription factors, which in turn may modify their DNA-binding properties in a promoter-specific fashion. Taken together, the gene-specific architecture of these unique complexes can mediate the selective control of transcriptional activity.
- SourceAvailable from: Cyndia Charfi
[Show abstract] [Hide abstract]
- "Detailed analysis of the apoD promoter also revealed the presence of an EBS and a Glucocorticoid Responsive Element (GRE) between the two SREs in the region −514 to −475 . The EBS, with its central core sequence 5'-GGA(A/T)-3', is known to cooperate tightly with the SRE through the binding of several nuclear proteins, particularly the Serum Response Factor (SRF) and members of the E26 transforming specific (ETS) family which regulate several genes implicated in cell proliferation and differentiation  . Also, the GRE is known to interact with the Glucocorticoid Receptor (GR), a nuclear receptor ligand-dependant transcription factor which recognizes the consensus sequence 5'-GGTACAnnnTGTTCT-3' . "
ABSTRACT: Human Apolipoprotein D (apoD) is upregulated under several stress conditions and pathological situations such as neurodegenerative diseases and cancers. We previously showed that apoD mRNA expression is induced in growth-arrested cells and demonstrated the specific binding of nuclear proteins to the region -514 to -475 of the promoter. Such region contains a pair of Serum Responsive Elements (SRE), an Ets-Binding Site (EBS) and a Glucocorticoid Responsive Element (GRE). In this study, we show that Parp-1, HnRNP-U, CBF-A, BUB-3, Kif4, APEX-1 and Ifi204 bind these regulatory elements of the apoD promoter. Specific binding of HnRNP-U and Parp-1 was confirmed by Electrophoretic Mobility Shift Assay (EMSA). In a biotin pull-down assay, Kif4 and BUB-3 bind preferentially the SRE1 and the EBS-GRE sites, respectively, while APEX-1 seems recruited indirectly to these elements. We found that the mRNA expression of some of these binding factors is upregulated in growth-arrested cells and that these proteins also transactivate the apoD promoter. In agreement with these results, mutants of APEX-1 and of Parp-1 defective for their DNA-binding and catalytic activities could not transactivate the promoter. The knockdown of Parp-1 and HnRNP-U and the use of specific inhibitors of MEK1/2 and of Parp-1 also inhibited the induction of apoD gene expression. Moreover, ERK1/2 was found activated in a biphasic manner post serum-starvation and the inhibition of Parp-1 causes a sustained activation of ERK2 but not ERK1 for up to 2h. Altogether, these findings demonstrate the importance of Parp-1, APEX-1 and ERK1/2 catalytic activities in the growth arrest-induced apoD gene expression.Biochimica et Biophysica Acta 09/2010; 1803(9):1062-71. DOI:10.1016/j.bbamcr.2010.04.011 · 4.66 Impact Factor
[Show abstract] [Hide abstract]
- "FGFs act by binding to their receptors and activating signal transduction pathways such as MAPK, PI3K or phospholipase C gamma . Phosphorylation of ETV5 by MAPK/ERKs increases DNA binding of ETV5 to its target genes   and alters gene expression   . Thus, in addition to being a transcriptional target of FGF, ETV5 also functions as a transcriptional effector within cells to transduce FGF signals . "
ABSTRACT: Ets variant gene 5 (ETV5) and glial cell-derived neurotrophic factor (GDNF) are produced in Sertoli cells and required for maintenance and self-renewal of spermatogonial stem cells (SSCs) in mice. Fibroblast growth factors (FGFs) have been reported to stimulate Etv5 mRNA expression, and FSH was shown to stimulate Gdnf mRNA in Sertoli cell cultures, but there is no other information on factors that regulate these key Sertoli cell proteins necessary for stem cell maintenance. In this study, we investigated regulation of ETV5 and GDNF using the TM4 murine Sertoli cell line. FGF2 stimulated a time- and dose-dependent increase in Etv5 mRNA expression, with a maximal 8.3-fold increase at 6 h following 25 ng/ml FGF2 treatment. This FGF2 dose also stimulated Gdnf mRNA at 48 h. FGF2 effects on Etv5 and Gdnf mRNA were partially mediated through mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K)-signaling cascades. Specific inhibitors of MAPK (PD98059) and PI3K (wortmannin) pathways reduced Etv5 and Gdnf mRNA expression in FGF2-treated cells. Epidermal growth factor (EGF) stimulated Etv5 mRNA but not Gdnf mRNA. TNFalpha and IL-1beta stimulated Gdnf mRNA, but had no effect on Etv5 mRNA. Other hormonal regulators of Sertoli cells such as testosterone, triiodothyronine and activin A did not affect Etv5 or Gdnf mRNA expression. Results with primary Sertoli cell cultures confirmed findings obtained with the TM4 cell line, validating the use of the TM4 model to examine regulation of Etv5 and Gdnf mRNA expression. In conclusion, we have identified common and unique pathways that regulate Etv5 and Gdnf mRNA in Sertoli cells, and FGFs are emerging as key regulators of the Sertoli cell proteins that control SSCs.Experimental Cell Research 09/2007; 313(14):3090-9. DOI:10.1016/j.yexcr.2007.05.002 · 3.37 Impact Factor
[Show abstract] [Hide abstract]
- "The oncogene v-ets was discovered as part of the gagmyb-ets fusion protein of the avian retrovirus E26, and is able to induce leukemia in vivo. The Ets transcription factor family consists of 27 members to date, all containing an 85 amino acid DNA-binding domain (the Ets domain) that confers the ability to bind to DNA sequences having the core motif GGAA/T (Ets-binding site, EBS)   . Another conserved area that is present in 11 members is the pointed (PNT) domain, which mediates protein-protein interactions and oligomerization . "
ABSTRACT: Ovarian cancer presents as disseminated disease in the majority of cases. Tumor metastasis to the peritoneal and/or pleural cavity is evident in two-thirds of cases at diagnosis and relapse is most often detected at this anatomic site. Despite the fact that the primary tumor is amenable to surgical removal in the majority of cases, ovarian cancer research, including the evaluation of therapeutic targets, has concentrated on primary disease. In recent years, we analyzed the site-dependent expression of cancer-associated and regulatory molecules in primary tumors, effusions and solid metastases. Our data show that some molecules (e.g., Ets transcription factors) are expressed at all anatomic sites in ovarian carcinoma and that their expression in primary and metastatic disease is associated with poor prognosis. However, the majority of molecules (e.g., cadherins, integrins, and nerve growth factor receptors) are differentially expressed along tumor progression and have different prognostic value depending on the organ sampled. Specifically, cancer-associated molecules with a well-characterized clinical significance in solid tumors (e.g., matrix metalloproteinases) have no such role in effusions. Finally, a growing number of molecules are differentially expressed in primary diagnosis (pre-chemotherapy) and disease recurrence (post-chemotherapy) specimens, reflecting the effect of disease progression and chemotherapy. This review will present the current knowledge in this area.Current cancer drug targets 03/2007; 7(1):109-20. DOI:10.2174/156800907780006904 · 3.58 Impact Factor