Functional analysis of a dominant-negative DeltaETS TEL/ETV6 isoform.

Abstract

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.

• Authors: Ko Sasaki, Yuka Nakamura, Kazuhiro Maki, Kazuo Waga, Fumihiko Nakamura, Honoka Arai, Yoichi Imai, Hisamaru Hirai, Kinuko Mitani
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 317 Issue 4 Pg. 1128-37 (May 14 2004) ISSN: 0006-291X [Print] United States
• PMID: 15094386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Protein Isoforms
• Proto-Oncogene Proteins c-ets
• Recombinant Proteins
• Repressor Proteins
• Tumor Suppressor Proteins

Topics

• Alternative Splicing
• Animals
• COS Cells
• Cell Differentiation
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• DNA-Binding Proteins (biosynthesis, chemistry, genetics, physiology)
• Dimerization
• Erythrocytes (cytology, metabolism)
• Genes, Dominant
• HeLa Cells
• Humans
• Leukocytes, Mononuclear (metabolism)
• Mice
• NIH 3T3 Cells
• Protein Isoforms
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-ets
• Recombinant Proteins (chemistry, genetics, metabolism)
• Repressor Proteins (biosynthesis, chemistry, genetics, physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Suppressor Proteins (chemistry, physiology)
• ETS Translocation Variant 6 Protein