The effect of mitogens on the mammalian cell cycle is opposed by the action of antimitogens. TGF-beta is the best known antimitogen, and inhibition of mammary tissue growth is its best known antiproliferative response in vivo. Our recent identification of TGF- beta receptors that initiate antimitogenic signals and of cell cycle kinase inhibitors that participate in the response to these signals, provide new insights into the mechanisms that inhibit cell proliferation. The evidence argues that mitogenic and antimitogenic signals confront each other by regulating in opposite ways the activity of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs) that control cell commitment to DNA replication. We propose to concentrate our studies on mammary epithelial cells in order to i) identify the TGF-beta receptor complexes that are present in these cells, and the ability of distinct receptor isoforms to specify antiproliferative responses; ii) determine the role of known CDKs and CKIs in mammary epithelial cell cycle control and their response to TGF-beta; iii) based on recent evidence that additional CKIs exist that are tissue-specific, we plan to molecularly clone and characterize novel CKIs from mammary epithelial cells. Given the importance of antimitogenic signaling pathways in cell cycle control, one may expect that losses in these pathways will contribute to oncogenic transformation. Indeed, resistance to the antiproliferative effects of TGF-beta and deranged CDK hyperactivity are often observed in human breast cancer cells. Therefore, we will iv) search for defects in TGF-beta signaling components in breast cancer. These studies will be best performed in the context of a programmatic project because i) the insights provided by the other participants in this project in the analysis of CKI responses to mitogen deprivation (Mendelsohn) and to anticancer agents (Koff), the regulatory circuits of p53 (Levine), and the identification of new tumor suppressor loci (Wigler), will help us focus our work on the most promising leads; and ii) we will contribute to others in this project novel antimitogenic signaling components that we expect to identify and clone in our studies. The translational research interest of this project is in two areas: i) the components of the antimitogenic pathways studied here are obvious models for the design of antiproliferative therapies, and ii) these components should be of predictive value of cancer therapy outcomes.
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