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v-SRC specifically regulates the nucleo-cytoplasmic delocalization of the major isoform of TEL (ETV6).
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2003 Oct 17; Vol. 278 (42), pp. 41316-25. Date of Electronic Publication: 2003 Jul 31. - Publication Year :
- 2003
-
Abstract
- TEL is a frequent target of chromosomal translocations in human cancer and an alleged tumor suppressor gene. TEL encodes two isoforms: a major TEL-M1 isoform as well as TEL-M43, which lacks the first 42 amino acid residues of TEL-M1. Both isoforms are potent transcriptional repressors that can inhibit RAS-induced transformation. Here we show that the v-SRC protein-tyrosine kinase relieves the repressive activity of TEL-M1, an activity that is associated with the v-SRC-induced delocalization of TEL-M1 from the nucleus to the cytoplasm. TEL-M1 delocalization requires the kinase activity of v-SRC and is not induced by oncogenic RAS or AKT. Cytoplasmic delocalization of TEL-M1 in response to v-SRC critically depends upon its unique amino-terminal domain (SRCD domain) because (i). v-SRC did not inhibit the repressive properties of TEL-M43, nor affected TEL-M43 nuclear localization; (ii). fusion of the first 52 amino acid residues of TEL-M1 to FLI-1, an ETS protein insensitive to v-SRC-induced delocalization, is sufficient to confer v-SRC-induced delocalization to this TEL/FLI-1 chimeric protein. The v-SRC-induced nucleo-cytoplasmic delocalization of TEL-M1 does not involve phosphorylation of the SRCD and does not require TEL self-association and repressive domains. Finally, enforced expression of the v-SRC-insensitive TEL-M43, but not of TEL-M1, inhibits v-SRC-induced transformation of NIH3T3 fibroblasts. These results identify a regulatory domain in TEL that specifically impinges on the subcellular localization of its major TEL-M1 isoform. They, furthermore, indicate that inhibition of TEL-M1 nuclear function is required for v-SRC to induce cellular transformation.
- Subjects :
- Animals
Blotting, Western
Chromosomes ultrastructure
DNA-Binding Proteins chemistry
Fibroblasts metabolism
Gene Expression Regulation, Enzymologic
Genetic Vectors
HeLa Cells
Humans
Luciferases metabolism
Mice
Microscopy, Fluorescence
NIH 3T3 Cells
Phosphorylation
Protein Isoforms
Protein Structure, Tertiary
Proto-Oncogene Proteins c-ets
Repressor Proteins chemistry
Time Factors
Transfection
ETS Translocation Variant 6 Protein
Cell Nucleus metabolism
Cytoplasm metabolism
DNA-Binding Proteins metabolism
Oncogene Protein pp60(v-src) metabolism
Oncogene Protein pp60(v-src) physiology
Repressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 278
- Issue :
- 42
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12893822
- Full Text :
- https://doi.org/10.1074/jbc.M306435200