Ets-1 p27: a novel Ets-1 isoform with dominant-negative effects on the transcriptional properties and the subcellular localization of Ets-1 p51.
The transcription factor Ets-1 is implicated in various physiological processes and invasive pathologies. We identified a novel variant of ets-1, ets-1Delta(III-VI), resulting from the alternative splicing of exons III to VI. This variant encodes a 27 kDa isoform, named Ets-1 p27. Ets-1 p27 lacks the threonine-38 residue, the Pointed domain and the transactivation domain, all of which are required for the transactivation of Ets-1 target genes. Both inhibitory domains surrounding the DNA-binding domain are conserved, suggesting that Ets-1 p27, like the full-length Ets-1 p51 isoform, is autoinhibited for DNA binding. We showed that Ets-1 p27 binds DNA in the same way as Ets-1 p51 does and that it acts both at a transcriptional and a subcellular localization level, thereby constituting a dual-acting dominant negative of Ets-1 p51. Ets-1 p27 blocks Ets-1 p51-mediated transactivation of target genes and induces the translocation of Ets-1 p51 from the nucleus to the cytoplasm. Furthermore, Ets-1 p27 overexpression represses the tumor properties of MDA-MB-231 mammary carcinoma cells in correlation with the known implication of Ets-1 in various cellular mechanisms. Thus the dual-acting dominant-negative function of Ets-1 p27 gives to the Ets-1 p27/Ets-1 p51 ratio a determining effect on cell fate.
Laitem
C
C
CNRS Unité Mixte de Recherche 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Universités de Lille 1 and Lille 2, IFR 142, Lille, France.
Leprivier
G
G
Choul-Li
S
S
Begue
A
A
Monte
D
D
Larsimont
D
D
Dumont
P
P
Duterque-Coquillaud
M
M
Aumercier
M
M
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005091:Exons / Q000235:genetics; D005260:Female; D005799:Genes, Dominant / Q000502:physiology*; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics* / Q000378:metabolism*; D011817:Rabbits; D012190:Retroviridae / Q000235:genetics; D013347:Subcellular Fractions; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D020033:Protein Isoforms; D050784:Proto-Oncogene Protein c-ets-1; D004247:DNA