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1.
Gene ; 591(1): 292-303, 2016 Oct 10.
Article in English | MEDLINE | ID: mdl-27421669

ABSTRACT

TEAD proteins constitute a family of highly conserved transcription factors, characterized by a DNA-binding domain called the TEA domain and a protein-binding domain that permits association with transcriptional co-activators. TEAD proteins are unable to induce transcription on their own. They have to interact with transcriptional cofactors to do so. Once TEADs bind their co-activators, the different complexes formed are known to regulate the expression of genes that are crucial for embryonic development, important for organ formation (heart, muscles), and involved in cell death and proliferation. In the first part of this review we describe what is known of the structure of TEAD proteins. We then focus on two members of the family: TEAD1 and TEAD2. First the different transcriptional cofactors are described. These proteins can be classified in three categories: i), cofactors regulating chromatin conformation, ii), cofactors able to bind DNA, and iii), transcriptional cofactors without DNA binding domain. Finally we discuss the recent findings that identified TEAD1 and 2 and its coactivators involved in cancer progression.


Subject(s)
DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Evolution, Molecular , Mammals/metabolism , Transcription Factors/chemistry , Transcription Factors/genetics , Animals , DNA-Binding Proteins/metabolism , Humans
2.
Dev Genes Evol ; 226(4): 297-315, 2016 07.
Article in English | MEDLINE | ID: mdl-27116603

ABSTRACT

The members of the vestigial-like gene family have been identified as homologs of the Drosophila vestigial, which is essential to wing formation. All members of the family are characterized by the presence of the TONDU domain, a highly conserved sequence that mediates their interaction with the transcription factors of the TEAD family. Mammals possess four vestigial-like genes that can be subdivided into two classes, depending on the number of Tondu domains present. While vestigial proteins have been studied in great depth in Drosophila, we still have sketchy knowledge of the functions of vestigial-like proteins in vertebrates. Recent studies have unveiled unexpected functions for some of these members and reveal the role they play in the Hippo pathway. Here, we present the current knowledge about vestigial-like family gene members and their functions, together with their identification in different taxa.


Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Evolution, Molecular , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Animals , Carrier Proteins , Co-Repressor Proteins/genetics , DNA-Binding Proteins/chemistry , Drosophila Proteins/genetics , Drosophila melanogaster , Gene Expression , Gene Expression Regulation , Humans , Muscle Proteins/genetics , Nuclear Proteins/chemistry , Protein Domains , Transcription Factors/genetics
3.
Hum Mol Genet ; 24(23): 6687-98, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26362254

ABSTRACT

Juvenile granulosa cell tumors (JGCTs) of the ovary are pediatric neoplasms representing 5% of all granulosa cell tumors (GCTs). Most GCTs are of adult type (AGCTs) and bear a mutation in the FOXL2 gene. The molecular basis of JGCTs is poorly understood, although mutations in the GNAS gene have been reported. We have detected in-frame duplications within the oncogene AKT1 in >60% of the JGCTs studied. Here, to evaluate the functional impact of these duplications and the existence of potential co-driver alterations, we have sequenced the transcriptome of four JGCTs and compared them with control transcriptomes. A search for gene variants detected only private alterations probably unrelated with tumorigenesis, suggesting that tandem duplications are the best candidates to underlie tumor formation in the absence of GNAS alterations. We previously showed that the duplications were specific to JGCTs. However, the screening of eight AGCTs samples without FOXL2 mutation showed the existence of an AKT1 duplication in one case, also having a stromal luteoma. The analysis of RNA-Seq data pinpointed a series of differentially expressed genes, involved in cytokine and hormone signaling and cell division-related processes. Further analyses pointed to the existence of a possible dedifferentiation process and suggested that most of the transcriptomic dysregulation might be mediated by a limited set of transcription factors perturbed by AKT1 activation. Finally, we show that commercially available AKT inhibitors can modulate the in vitro activity of various mutated forms. These results shed light on the pathogenesis of JGCTs and provide therapeutic leads for a targeted treatment.


Subject(s)
Granulosa Cell Tumor/genetics , Mutation , Ovarian Neoplasms/genetics , Proto-Oncogene Proteins c-akt/genetics , Adolescent , Cell Division/genetics , Child , Child, Preschool , Cytokines , DNA Mutational Analysis , Female , Gene Expression Profiling , Gene Expression Regulation , Granulosa Cell Tumor/metabolism , Hormones , Humans , Infant , Infant, Newborn , Ovarian Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Signal Transduction/genetics
4.
Elife ; 32014 Nov 04.
Article in English | MEDLINE | ID: mdl-25369636

ABSTRACT

FOXL2 is a lineage determining transcription factor in the ovary, but its direct targets and modes of action are not fully characterized. In this study, we explore the targets of FOXL2 and five nuclear receptors in murine primary follicular cells. We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells. Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element. Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression. Altogether, we show that FOXL2 mobilizes estrogen signaling to establish a coherent feed-forward loop repressing Sox9. This sheds a new light on the role of FOXL2 in ovarian maintenance and function.


Subject(s)
Estrogens/metabolism , Forkhead Transcription Factors/metabolism , Granulosa Cells/cytology , Granulosa Cells/metabolism , Signal Transduction , Animals , Cells, Cultured , Estradiol/pharmacology , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Female , Forkhead Box Protein L2 , Forkhead Transcription Factors/genetics , Gene Expression Regulation/drug effects , Gene Regulatory Networks/drug effects , Genome , Granulosa Cells/drug effects , Mice , Receptors, Cytoplasmic and Nuclear/metabolism , Regulatory Sequences, Nucleic Acid/genetics , Signal Transduction/drug effects , Transcription, Genetic/drug effects , Transcriptome/drug effects , Transcriptome/genetics
5.
FEBS Lett ; 587(19): 3216-23, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23994529

ABSTRACT

Although the expression of the neuronal apoptosis inhibitory protein (NAIP) gene is considered involved in apoptosis suppression as well as in inflammatory response, the molecular basis of the NAIP gene expression is poorly understood. Here we show that the TEA domain protein 1 (TEAD1) is able to positively activate the transcription of NAIP. We further demonstrate that this regulation is mediated by the presence of the endogenous Yes associated protein (YAP) cofactor, and requires the interaction with YAP. We finally identified an intronic region of the NAIP gene responding to TEAD1/YAP activity, suggesting that regulation of NAIP by TEAD1/YAP is at the transcriptional level.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Neuronal Apoptosis-Inhibitory Protein/genetics , Nuclear Proteins/metabolism , Phosphoproteins/metabolism , Transcription Factors/metabolism , Base Sequence , Cell Line, Tumor , DNA , DNA-Binding Proteins/physiology , Humans , Molecular Sequence Data , Nuclear Proteins/physiology , Protein Binding , TEA Domain Transcription Factors , Transcription Factors/physiology , Transcription, Genetic , YAP-Signaling Proteins
6.
FASEB J ; 27(4): 1330-41, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23271049

ABSTRACT

Scalloped (SD) is a transcription factor characterized by a TEA/ATTS DNA binding domain. To activate transcription, SD must interact with its coactivators, including Yorkie (YKI) or Vestigial (VG). YKI is the downstream effector of the Hippo signaling pathway that plays a key role in the control of tissue growth. The core components of this pathway are two kinases, Hippo (HPO) and Warts (WTS), which negatively regulate the activity of the SD/YKI complex, retaining YKI in the cytoplasm. We previously showed that HPO kinase can also reduce SD/VG transcriptional activity in Drosophila S2 cells. We further investigated the relationship between the SD/VG complex and the Hippo pathway. We show here that HPO overexpression suppresses overgrowth induced by SD/VG in vivo during Drosophila development. Using S2 cells, we show that HPO promotes the translocation of SD to the cytoplasm in a CRM1-dependent manner, thereby inhibiting the induction of SD/VG target genes. Using RNAi-mediated depletion of yki and a mutant SD protein unable to interact with YKI, we demonstrate that HPO regulates SD localization independently of YKI. This function requires HPO kinase activity, yet surprisingly, not its downstream effector kinase WTS. Taken together, these observations reveal a new and unexpected role of HPO kinase in the regulation of a transcription factor independently of YKI.


Subject(s)
Cytoplasm/metabolism , Drosophila Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Karyopherins/metabolism , Protein Serine-Threonine Kinases/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/metabolism , Animals , Cell Proliferation , Drosophila , Drosophila Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Signal Transduction/genetics , Transcription Factors/genetics , Transcription, Genetic/physiology , Warts/genetics , Warts/metabolism , Exportin 1 Protein
7.
PLoS One ; 7(9): e45498, 2012.
Article in English | MEDLINE | ID: mdl-23029054

ABSTRACT

BACKGROUND: TEA domain (TEAD) proteins are highly conserved transcription factors involved in embryonic development and differentiation of various tissues. More recently, emerging evidences for a contribution of these proteins towards apoptosis and cell proliferation regulation have also been proposed. These effects appear to be mediated by the interaction between TEAD and its co-activator Yes-Associated Protein (YAP), the downstream effector of the Hippo tumour suppressor pathway. METHODOLOGY/PRINCIPAL FINDINGS: We further investigated the mechanisms underlying TEAD-mediated apoptosis regulation and showed that overexpression or RNAi-mediated silencing of the TEAD1 protein is sufficient to protect mammalian cell lines from induced apoptosis, suggesting a proapoptotic function for TEAD1 and a non physiological cytoprotective effect for overexpressed TEAD1. Moreover we show that the apoptotic resistance conferred by altered TEAD1 expression is mediated by the transcriptional up-regulation of Livin, a member of the Inhibitor of Apoptosis Protein (IAP) family. In addition, we show that overexpression of a repressive form of TEAD1 can induce Livin up-regulation, indicating that the effect of TEAD1 on Livin expression is indirect and favoring a model in which TEAD1 activates a repressor of Livin by interacting with a limiting cofactor that gets titrated upon TEAD1 up-regulation. Interestingly, we show that overexpression of a mutated form of TEAD1 (Y421H) implicated in Sveinsson's chorioretinal atrophy that strongly reduces its interaction with YAP as well as its activation, can induce Livin expression and protect cells from induced apoptosis, suggesting that YAP is not the cofactor involved in this process. CONCLUSIONS/SIGNIFICANCE: Taken together our data reveal a new, Livin-dependent, apoptotic role for TEAD1 in mammals and provide mechanistic insight downstream of TEAD1 deregulation in cancers.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Apoptosis/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation , Inhibitor of Apoptosis Proteins/genetics , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Transcription, Genetic , Alternative Splicing , Cell Line , Epistasis, Genetic , HeLa Cells , Humans , RNA Isoforms , TEA Domain Transcription Factors
8.
Dev Biol ; 332(2): 258-72, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19500564

ABSTRACT

The gene vestigial (vg) plays a key role in indirect flight muscle (IFM) development. We show here that vg is controlled by the Notch anti-myogenic signaling pathway in myoblasts and is regulated by a novel 822 bp enhancer during IFM differentiation. Interestingly, this muscle enhancer is activated in developing fibers and in a small number of myoblasts before the fusion of myoblasts with the developing muscle fibers. Moreover, we show that this enhancer is activated by Drosophila Myocyte enhancing factor 2 (MEF2), Scalloped (SD) and VG but repressed by Twist, demonstrating a sensitivity to differentiation in vivo. In vitro experiments reveal that SD can directly bind this enhancer and MEF2 can physically interact with both SD and TWI. Cumulatively, our data reveal the interplay between different myogenic factors responsible for the expression of an enhancer activated during muscle differentiation.


Subject(s)
Cell Differentiation/physiology , Drosophila Proteins/genetics , Drosophila melanogaster , Enhancer Elements, Genetic , Gene Expression Regulation, Developmental , Nuclear Proteins/genetics , Signal Transduction/physiology , Animals , Cell Line , Drosophila Proteins/metabolism , Drosophila melanogaster/anatomy & histology , Drosophila melanogaster/embryology , Drosophila melanogaster/genetics , Flight, Animal , Muscles/embryology , Muscles/physiology , Myoblasts/cytology , Myoblasts/physiology , Myogenic Regulatory Factors/genetics , Myogenic Regulatory Factors/metabolism , Nuclear Proteins/metabolism , Receptors, Notch/genetics , Receptors, Notch/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Twist-Related Protein 1/genetics , Twist-Related Protein 1/metabolism
9.
Curr Biol ; 18(6): 435-41, 2008 Mar 25.
Article in English | MEDLINE | ID: mdl-18313299

ABSTRACT

In Drosophila, SCALLOPED (SD) belongs to a family of evolutionarily conserved proteins characterized by the presence of a TEA/ATTS DNA-binding domain [1, 2]. SD physically interacts with the product of the vestigial (vg) gene, where the dimer functions as a master gene controlling wing formation [3, 4]. The VG-SD dimer activates the transcription of several specific wing genes, including sd and vg themselves [5, 6]. The dimer drives cell-cycle progression by inducing expression of the dE2F1 transcription factor [7], which regulates genes involved in DNA replication and cell-cycle progression. Recently, YORKIE (YKI) was identified as a transcriptional coactivator that is the downstream effector of the Hippo signaling pathway, which controls cell proliferation and apoptosis in Drosophila[8]. We identified SD as a partner for YKI. We show that interaction between YKI and SD increases SD transcriptional activity both ex vivo in Drosophila S2 cells and in vivo in Drosophila wing discs and promotes YKI nuclear localization. We also show that YKI overexpression induces vg and dE2F1 expression and that proliferation induced by YKI or by a dominant-negative form of FAT in wing disc is significantly reduced in a sd hypomorphic mutant context. Contrary to YKI, SD is not required in all imaginal tissues. This indicates that YKI-SD interaction acts in a tissue-specific fashion and that other YKI partners must exist.


Subject(s)
Drosophila Proteins/metabolism , Drosophila/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Trans-Activators/metabolism , Transcription Factors/metabolism , Wings, Animal/growth & development , Animals , Cell Proliferation , Drosophila/growth & development , HeLa Cells , Humans , Morphogenesis/physiology , Protein Kinases/metabolism , Signal Transduction/physiology , Tumor Suppressor Proteins/metabolism , YAP-Signaling Proteins
10.
Dev Dyn ; 232(3): 725-32, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15704138

ABSTRACT

Lipid droplets are the major neutral lipid storage organelles in higher eukaryotes. The PAT domain proteins (Perilipin, ADRP [adipose differentiation related protein], and TIP47 [tail-interacting 47-kDa protein]) are associated with these structures. Perilipin and ADRP are involved in the regulation of lipid storage and metabolism in mammals. Two genes encoding PAT proteins, Drosophila Lipid Storage Droplet 2 Gene (Lsd-2) and Lsd-2, have been identified in Drosophila. Lsd-2 is expressed in fat bodies and in the female germ line and is involved in lipid storage in these tissues. We showed that Lsd-2 is expressed in third-instar wing imaginal discs in Drosophila, with higher levels in the wing pouch, which corresponds to the presumptive wing region of the wing disc. This specific expression pattern is correlated with a high level of neutral lipid accumulation. We also showed that neutral lipid deposition in the wing disc is severely reduced in an Lsd-2 mutant and is increased with Lsd-2 overexpression. Finally, we showed that overexpression of the vestigial (vg) pro-wing gene induces Lsd-2 expression, suggesting that Lsd-2 mediates a vg role during wing formation. Our results suggest that Lsd-2 function is not restricted to tissues directly involved in lipid storage and could play additional roles during development.


Subject(s)
Drosophila Proteins/metabolism , Drosophila/growth & development , Genes, Insect , Lipid Metabolism , Wings, Animal/growth & development , Animals , Carrier Proteins , Drosophila/embryology , Drosophila/genetics , Drosophila Proteins/genetics , Embryo, Nonmammalian , Fat Body/embryology , Fat Body/growth & development , Fat Body/metabolism , Larva/growth & development , Larva/metabolism , Metamorphosis, Biological , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Perilipin-1 , Phosphoproteins/metabolism , Wings, Animal/cytology
11.
Genes Cells ; 7(12): 1255-66, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12485165

ABSTRACT

BACKGROUND: Compartment formation is a developmental process that requires the existence of barriers against intermixing between cell groups. In the Drosophila wing disc, the dorso-ventral (D/V) compartment boundary is defined by the expression of the apterous (ap) selector gene in the dorsal compartment. AP activity is under control of dLMO which destabilizes the formation of the AP-CHIP complex. RESULTS: We report that D/V boundary formation in the wing disc also depends on early expression of vestigial (vg). Our data suggest that vg is already required for wing cell proliferation before D/V compartmentalization. In addition, we show that over-expression of vg can, to some extent, rescue the effect of the absence of ap on D/V boundary formation. Early VG product regulates AP activity by inducing dLMO and thus indirectly regulating ap target genes such as fringe and the PSalpha1 and PSalpha2 integrins. CONCLUSION: Normal cell proliferation is necessary for ap expression at the level of the D/V boundary. This would be mediated by vg, which interacts in a dose-dependent way with ap.


Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Gene Expression Regulation, Developmental , Homeodomain Proteins/metabolism , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Animals , Cell Division/physiology , Drosophila Proteins/genetics , Drosophila melanogaster/anatomy & histology , Drosophila melanogaster/genetics , Integrin alpha Chains , Integrins/genetics , Integrins/metabolism , LIM-Homeodomain Proteins , Morphogenesis , N-Acetylglucosaminyltransferases/genetics , N-Acetylglucosaminyltransferases/metabolism , Nuclear Proteins/genetics , Phenotype , Wings, Animal/cytology , Wings, Animal/growth & development , Wings, Animal/physiology
12.
Dev Growth Differ ; 38(5): 557-564, 1996 Oct.
Article in English | MEDLINE | ID: mdl-37281251

ABSTRACT

Suppressor genes of the vestigial phenotype have been isolated in a wild-type population. These suppressors have an effect on different wing mutants and are allele-specific in the case of vestigial. In a vgBG background they produced overgrowth of the imaginal wing disc. They also induce cell death in the wild-type strain and alter the distribution of cell death in the mutant strain. Expression of vestigial is increased in the wing disc only. Hypotheses formed to determine the nature of these suppressors are in favor of a direct interaction between these genes and vestigial.

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