Scientific Report 2005

Immunology

Regulatory Mechanisms for Tumor Carcinogenesis

M. Hayashi, J.-F. Lo, S.-W. Kim, J.-D. Lee

The Fourth Map Kinase Pathway

Big mitogen-activated kinase 1 (BMK1), also called extracellular signal–regulated kinase 5, a newer member of the mammalian MAP kinase family, is activated by angiogenic growth factors. Using a mouse model in which expression of the gene for BMK1 can be deleted, we showed that the BMK1 pathway delivers an antiapoptotic signal in endothelial cells and plays a critical role in neovascularization during development and in response to stimulation by angiogenic growth factors. Our recent data suggest that BMK1 regulates the function of endothelial cells not only at the transcriptional level but also at the translational level. Because endothelial cells are a key component in the vasculature and are important for the formation of new blood vessels, most likely the BMK1 pathway regulates angiogenesis through its function in endothelial cells.

Moreover, because angiogenesis contributes to tumor growth, we hypothesize that the BMK1 pathway is involved in tumor-induced neovascularization, which is vital for sustaining tumor growth. To shed light on the role of the BMK1 pathway in various aspects of cancer development, we use multidisciplinary approaches, including molecular, cellular, genetic, and pathologic methods, to elucidate the molecular mechanisms of BMK1 in angiogenesis and oncogene-dependent tumorigenesis. The results will provide insights into new strategies for therapeutic interventions of carcinogenesis.

The Tumor Suppressor Tid1

Tid1 is the human counterpart of the Drosophila tumor suppressor Tid56. Mutations that cause loss of function of the gene for Tid56 result in tumorous imaginal discs due to continuous cell proliferation without differentiation. To date, the mechanism of tumor suppression of Tid56 in Drosophila and the cellular function of Tid1 in human tumorigenesis are poorly understood. We discovered that the signaling domain of the receptor protein-tyrosine kinase ErbB2 interacts with Tid1 protein. We also found that increased expression of Tid1 in breast cancer cells overexpressing ErbB2 promotes ubiquitinization and proteosomal degradation of ErbB2, resulting in potent inhibition of ErbB2-dependent intracellular signaling and proliferation/survival of the cells.

To evaluate and characterize the role of Tid1 in breast tumorigenesis in adult animals, we have established a mouse model in which the gene for Tid1 can be deleted specifically in mammary epithelial cells. These animals can be used to closely mimic the effect in humans of Tid1 removal on the onset and progression of breast cancer associated with Tid1 dysfunction. The mice can also be used to screen and test agents used for treatment of breast tumors involving a Tid1 defect.

Publications

Hayashi, M.. Lee, J.-D. Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J. Mol. Med. 82:800, 2004.

Kim, S.-W, Chao, T.H., Xiang, R., Lo, J.F., Campbell, M.J., Fearns, C., Lee, J.-D. Tid1, the human homologue of a Drosophila tumor suppressor, reduces the malignant activity of ErbB-2 in carcinoma cells. Cancer Res. 24:7732, 2004.

Lo, J.F., Zhou, H., Fearns, C., Reisfeld, R.A., Yang, Y., Lee, J.-D. Tid1 is required for T cell transition from double-negative 3 to double-positive stages. J. Immunol. 174:6105, 2005.