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Retinoic acid inhibits transformation by preventing phosphatidylinositol 3-kinase dependent activation of the c-fos promoter

Oncogene volume 18, pages 139–148 (1999)Cite this article

Abstract

Retinoic acid inhibits transformation of cells by polyoma virus middle T oncoprotein. Inhibition of transformation results from a retinoic acid-dependent failure of cells to fully express the c-fos proto-oncogene. Retinoic acid prevents transactivation of the c-fos promoter by disrupting signaling between tyrosine kinases at the plasma membrane and trans-acting factors at the c-fos promoter. We used complementary genetic, biochemical and molecular approaches to demonstrate that: (1) phosphatidylinositol 3-kinase signaling is the principle mechanism of polyoma virus middle T oncoprotein activation of c-fos expression; (2) middle T/phosphatidylinositol 3-kinase transactivation of the c-fos promoter and transformation of cells requires activation of both the small GTP-binding protein Rac and Jun N-terminal kinase; (3) retinoic acid inhibits activation of Jun N-terminal kinase, thereby preventing c-fos transactivation and transformation; and (4) middle T activation of c-fos transcription requires both the serum response element and the promoter proximal cyclic AMP response element. These studies identify a novel target through which retinoids prevent oncogenic transformation.

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Acknowledgements

The authors would like to thank Drs A Minden, R Prywes, J Blenis and G Viglianti for plasmids and other reagents and Dr Audrey Minden for comments on the manuscript. These studies were supported by grants from the American Cancer Society (RPG95-024-03-CN, to DAT), the American Institute for Cancer Research (to DAT); the Columbia Presbyterian Cancer Center (to DAT) and the National Institute of Health (CA63111 to RF).

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  1. Mark Listerud: Deceased

Authors and Affiliations

  1. Institute of Human Nutrition, Columbia University, New York, New York, USA

    Yachi Chen, Mark Listerud, Zuohong Wang & David A Talmage

  2. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA

    Robert Freund

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Chen, Y., Freund, R., Listerud, M. et al. Retinoic acid inhibits transformation by preventing phosphatidylinositol 3-kinase dependent activation of the c-fos promoter. Oncogene 18, 139–148 (1999). https://doi.org/10.1038/sj.onc.1202272

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