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1.
Bull Cancer ; 93(10): 985-9, 2006 Oct.
Article in French | MEDLINE | ID: mdl-17074657

ABSTRACT

Erm, Er81, and Pea3 are the three members of the PEA3 group which belong to the Ets transcription factors family. These proteins regulate transcription of multiple target genes, such as those encoding several matrix metalloproteinases (MMP), which are enzymes degrading the extracellular matrix during cancer metastasis. In fact, PEA3-group genes are often overexpressed in different types of human cancers that also over-express these MMP and display a disseminating phenotype. In experimental models, regulation of PEA3 group member expression has been shown to influence the metastatic process, thus suggesting that these factors play a key role in metastasis.


Subject(s)
Matrix Metalloproteinases/metabolism , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Transcription Factors/metabolism , Transcription, Genetic , Animals , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Rearrangement/genetics , Humans , Mice , Neoplasm Metastasis , Neoplasm Proteins/genetics , Neoplasms/pathology , Proto-Oncogene Proteins c-ets/genetics , Proto-Oncogene Proteins c-ets/metabolism , Transcription Factors/genetics
2.
Biochim Biophys Acta ; 1766(1): 79-87, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16546322

ABSTRACT

The PEA3 group is composed of three highly conserved Ets transcription factors: Erm, Er81, and Pea3. These proteins regulate transcription of multiple genes, and their transactivating potential is affected by post-translational modifications. Among their target genes are several matrix metalloproteases (MMPs), which are enzymes degrading the extracellular matrix during normal remodelling events and cancer metastasis. In fact, PEA3-group genes are often over-expressed in different types of cancers that also over-express these MMPs and display a disseminating phenotype. Experimental regulation of the synthesis of PEA3 group members influences the metastatic process. This suggests that these factors play a key role in metastasis.


Subject(s)
Neoplasm Metastasis/genetics , Neoplasms/genetics , Proto-Oncogene Proteins c-ets/genetics , Transcription Factors/genetics , Animals , Gene Expression Regulation, Neoplastic , Humans , Neoplasms/pathology
3.
Oncogene ; 22(21): 3319-29, 2003 May 22.
Article in English | MEDLINE | ID: mdl-12761502

ABSTRACT

Although most Ets transcription factors have been characterized as transcriptional activators, some of them display repressor activity. Here we characterize an Ets-family member, the very specifically expressed human Fifth Ewing Variant (FEV), as a transcriptional repressor. We show that among a broad range of human cell lines, only Dami megakaryocytic cells express FEV. This nuclear protein binds to Ets-binding sites, such as that of the human ICAM-1 promoter. We used this promoter to demonstrate that FEV can repress both basal transcription and, even more strongly, ectopically Ets-activated transcription. We identified two domains responsible for FEV-mediated repression: the ETS domain, responsible for passive repression, and the carboxy-terminal alanine-rich domain, involved in active repression. In the Ets-independent LEXA system also, FEV acts as a transcriptional repressor via its alanine-rich carboxy-terminal domain. The mechanism by which FEV actively represses transcription is currently unknown, since FEV-triggered repression is not reversed by the histone deacetylase inhibitor trichostatin A. We also showed that long-term overexpression of FEV proteins containing the alanine-rich domain prevents cell clones from growing, whereas clones expressing a truncated FEV protein lacking this domain develop like control cells. This confirms the importance of this domain in FEV-triggered repression.


Subject(s)
Alanine/analysis , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/physiology , Gene Silencing , Nuclear Proteins/chemistry , Nuclear Proteins/physiology , Repressor Proteins/chemistry , Repressor Proteins/physiology , Animals , COS Cells , Cell Line , Cell Nucleus/chemistry , DNA-Binding Proteins/genetics , Humans , Nuclear Proteins/genetics , Protein Structure, Tertiary , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-ets , Rabbits , Response Elements , Transcription Factors/antagonists & inhibitors , Transcription Factors/chemistry , Transcription Factors/metabolism , Transcription, Genetic , Transfection , Tumor Cells, Cultured
4.
J Biol Chem ; 277(2): 1002-12, 2002 Jan 11.
Article in English | MEDLINE | ID: mdl-11682477

ABSTRACT

The final step of the transduction pathway is the activation of gene transcription, which is driven by kinase cascades leading to changes in the activity of many transcription factors. Among these latter, PEA3/E1AF, ER81/ETV1, and ERM, members of the well conserved PEA3 group from the Ets family are involved in these processes. We show here that protein kinase A (PKA) increases the transcriptional activity of human ERM and human ETV1, through a Ser residue situated at the edge of the ETS DNA-binding domain. PKA phosphorylation does not directly affect the ERM transactivation domains but does affect DNA binding activity. Unphosphorylated wild-type ERM bound DNA avidly, whereas after PKA phosphorylation it did so very weakly. Interestingly, S367A mutation significantly reduced the ERM-mediated transcription in the presence of the kinase, and the DNA binding of this mutant, although similar to that of unphosphorylated wild-type protein, was insensitive to PKA treatment. Mutations, which may mimic a phosphorylated serine, converted ERM from an efficient DNA-binding protein to a poor DNA binding one, with inefficiency of PKA phosphorylation. The present data clearly demonstrate a close correlation between the capacity of PKA to increase the transactivation of ERM and the drastic down-regulation of the binding of the ETS domain to the targeted DNA. What we thus demonstrate here is a relatively rare transcription activation mechanism through a decrease in DNA binding, probably by the shift of a non-active form of an Ets protein to a PKA-phosphorylated active one, which should be in a conformation permitting a transactivation domain to be active.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , DNA-Binding Proteins/metabolism , Transcription Factors/metabolism , Transcriptional Activation , Up-Regulation , Amino Acid Sequence , Animals , Cell Line , Collagenases/genetics , Collagenases/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Humans , Molecular Sequence Data , Phosphorylation , Promoter Regions, Genetic , Protein Binding , Protein Structure, Tertiary , Rabbits , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Alignment , Signal Transduction/physiology , Transcription Factors/chemistry , Transcription Factors/genetics
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