Mutation in the DNA-binding domain of the EWS-Oct-4 oncogene results in dominant negative activity that interferes with EWS-Oct-4-mediated transactivation

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The EWS-Oct-4 protein is a chimeric molecule in which the amino terminal domain (NTD) of the EWS becomes fused to the carboxy terminal domain (CTD) of the Cict-4 transcription factor. It was identified in human bone and soft-tissue tumors associated with t(6;22)(p21;q12). Using in vitro and in vivo systems, we found that the EWS-Oct-4 protein self-associates. The major domains required for self-association mapped to the EWS NTD (amino acids 70-163) and the POU DNA-binding domain. EWS-Oct-4 protein also associated with EWS-Oct-4 (V351P), which contains a mutation in the POU DNA-binding domain. Using electrophoretic mobility shift assays, we found that the EWS-Oct-4 (V351P) mutant interfered with wild-type EWS-Oct-4 DNA-binding activity. In addition, we found that EWS-Oct-4-mediated transcriptional activation was inhibited by EWS-Oct-4 (V351P) protein in vivo. Thus, this mutation in the POU DNA-binding domain results in a dominant negative protein. These findings suggest that the biological functions of the EWS-Oct-4 oncogene can be modulated by the dominant negative mutant EWS-Oct-4 (V351P). (C) 2008 Wiley-Liss, Inc.
Publisher
WILEY-LISS
Issue Date
2009-05
Language
English
Article Type
Article
Keywords

GERM-CELL TUMORS; EWINGS-SARCOMA PROTEIN; BREAST-CANCER CELLS; RNA-POLYMERASE-II; TRANSCRIPTION FACTOR; EMBRYONIC GENES; STEM-CELLS; POU-DOMAIN; OCT-4; EWS

Citation

INTERNATIONAL JOURNAL OF CANCER, v.124, no.10, pp.2312 - 2322

ISSN
0020-7136
DOI
10.1002/ijc.24228
URI
http://hdl.handle.net/10203/97321
Appears in Collection
BS-Journal Papers(저널논문)
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