A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein.
TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. We show here by co-immunoprecipitation and GST chromatography analyses that TEL and TEL-derived fusion proteins form homotypic oligomers in vitro and in vivo. Deletion mutagenesis identifies the TEL oligomerization domain as a 65 amino acid region which is conserved in a subset of the ETS proteins including ETS-1, ETS-2, FLI-1, ERG-2 and GABP alpha in vertebrates and PNTP2, YAN and ELG in Drosophila. TEL-induced oligomerization is shown to be essential for the constitutive activation of the protein kinase activity and mitogenic properties of TEL-platelet derived growth factor receptor beta (PDGFR beta), a fusion oncoprotein characteristic of the leukemic cells of chronic myelomonocytic leukemia harboring a t(5;12) chromosomal translocation. Swapping experiments in which the TEL oligomerization domain was exchanged by the homologous domains of representative vertebrate ETS proteins including ETS-1, ERG-2 and GABP alpha show that oligomerization is a specific property of the TEL amino-terminal conserved domain. These results indicate that the amino-terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein-protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators.
Jousset
C
C
CNRS UMR 146, Institut Curie-Section de Recherche, Centre Universitaire, Orsay, France.
Carron
C
C
Boureux
A
A
Quang
C T
CT
Oury
C
C
Dusanter-Fourt
I
I
Charon
M
M
Levin
J
J
Bernard
O
O
Ghysdael
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002455:Cell Division; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D004330:Drosophila; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000502:physiology*; D012097:Repressor Proteins; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D015513:Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein