Abstract
Misexpression of the dorsal mesodermal patterning factor goosecoid on the ventral side of amphibian embryos results in inhibition of blood formation in early embryogenesis. To investigate the mechanism of this inhibition, we ectopically expressed goosecoid in erythroleukemia cells. While erythroid differentiation of these cells can be induced by activin, goosecoid expressing cells were unresponsive to activin. We demonstrate an in vitro interaction between the oncogene PU.1, an ets family transcription factor thought to play a role in erythropoiesis, and the goosecoid protein (GSC). Interaction with PU.1 was specific as GSC did not bind to the ets family members, Fli-1 or Ets-2. The ability of goosecoid expressing erythroleukemia cells to differentiate in response to activin was rescued by coexpression of the GSC-binding N-terminal portion of PU.1. The N-terminal portion of PU.1 was co-immunoprecipitated with anti-GSC antibodies as well. The N-terminal domain of PU.1 is the region recognized by the retinoblastoma protein (Rb), a tumor suppressor gene presumably involved in erythroid differentiation. We show that GSC competitively inhibits binding of Rb to PU.1. Our data suggest that the suppression of blood formation by GSC could, at least in part, be mediated by binding to PU.1.
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Acknowledgements
We are grateful to Dr Yuzuru Eto for the generous supply of activin and F5-5 cells. We are also grateful to Dr Robert Weinberg for the generous supply of mouse Rb gene and Drs Dennis Templeton and Masanori Hatakeyama for information about Rb. We appreciate the continuous encouragement of Drs Tomio Tada, Toshio Kuroki, the former president of Kochi Medical School, Isamu Kitamura and the president of Kochi Medical School, Hisao Ikeda. We also appreciate Daniel B Ribble for critical reading of this manuscript. This work was supported in part by Grants-in-Aid for Scientific Research and Grants-in-Aid for Special Project Research, Cancer Biology, from the Japanese Ministry of Education, Science, and Culture and also supported by Kochi Medical School President Research Fund.
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Konishi, Y., Tominaga, M., Watanabe, Y. et al. GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1 binding in murine cells. Oncogene 18, 6795–6805 (1999). https://doi.org/10.1038/sj.onc.1203118
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DOI: https://doi.org/10.1038/sj.onc.1203118