Functional analysis of a dominant-negative DeltaETS TEL/ETV6 isoform.
A transcriptional repressor TEL belongs to the ETS family transcription factors and acts as a tumor suppressor. We identified five alternatively spliced TEL isoforms generated possibly through exon skipping mechanisms, by using reverse transcriptase-polymerase chain reaction analysis. Among them, we examined molecular and biological functions of a DeltaETS-TEL isoform (TEL-f). This isoform abrogated specific DNA-binding capacity to and trans-repressional ability through the ETS-binding site. Regardless, it showed dominant-negative effects over wild-type-TEL (TEL-a)-mediated transcriptional repression partly through sequestration of TEL-a from nucleus to cytoplasm. Moreover, TEL-f dominantly interfered with TEL-a-mediated erythroid differentiation in MEL cells and growth suppression in NIH3T3 cells. Interestingly, TEL isoforms without the entire (Delta exons 6+7-TEL) or a part (Delta exon 7-TEL) of ETS domain were expressed more frequently in myelodysplastic syndrome-derived leukemia than in myelodysplastic syndrome before transformation. This observation suggests that accumulation of the dominant-negative DeltaETS-TEL molecules could be a related phenomenon to leukemic progression of myelodysplastic syndrome.
Sasaki
Ko
K
Department of Hematology, Dokkyo University School of Medicine, Tochigi 321-0293, Japan.
Nakamura
Yuka
Y
Maki
Kazuhiro
K
Waga
Kazuo
K
Nakamura
Fumihiko
F
Arai
Honoka
H
Imai
Yoichi
Y
Hirai
Hisamaru
H
Mitani
Kinuko
K
D017398:Alternative Splicing; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019281:Dimerization; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D050783:Proto-Oncogene Proteins c-ets; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000502:physiology; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D050783:Proto-Oncogene Proteins c-ets; D011994:Recombinant Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D000097764:ETS Translocation Variant 6 Protein