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
- Authors
- Kim, Sol; Lee, Jungwoon; Kim, Ja Young; Lim, Bobae; Shin, Eung-Kyun; Han, Yong-Mahn; Kim, Sung-Su; Song, Jin-Ho; Kirn, Jungho
- Issue Date
- May-2009
- Publisher
- WILEY
- Keywords
- EWS-Oct-4; self-association; dominant negative; chromosomal translocation; transactivation; transformation; bone and soft-tissue tumors
- Citation
- INTERNATIONAL JOURNAL OF CANCER, v.124, no.10, pp 2312 - 2322
- Pages
- 11
- Journal Title
- INTERNATIONAL JOURNAL OF CANCER
- Volume
- 124
- Number
- 10
- Start Page
- 2312
- End Page
- 2322
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/23182
- DOI
- 10.1002/ijc.24228
- ISSN
- 0020-7136
1097-0215
- Abstract
- 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.
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