The Function of PNUTS (Phosphatase Nuclear Targeting Subunit) in the Cell Cycle

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DESCRIPTION (provided by applicant): In cancer cells, division and replication occurs in the absence of signals to do so. Many proteins that control cell division are involved in cancer development. The activity of the tumor suppressor protein, Retinoblastoma (Rb), is often deregulated in cancer cells. Rb inhibits proliferation in cells in which it is active, but allows cell proliferation when it is inactive. Rb activity is controlled by its phosphorylation state which is regulated by cyclin dependent kinases (cdks) and Protein phosphatase 1 (PP1). PP1 activity is controlled by targeting subunits that bind to and direct it to specific substrates. There is a newly identified PP1-targeting subunit called PNUTS (Phosphatase Nuclear Targeting Subunit) which inhibits PP1 activity toward Rb in vitro. The PNUTS protein is highly expressed in two types of breast cancer cells, therefore the specific aims of this project are designed to elucidate the function of and regulation of PNUTS in cell cycle control. To investigate the role of PNUTS in the cell division cycle, we intend to use RNA interference (RNAi) to block PNUTS expression in breast cancer cells and examine the effects on the enzyme activity of PP1, Rb phosphorylation status and cell proliferation. In addition, the regulation of PNUTS activity by phosphorylation and its association with PP1 will be investigated. The elucidation of PNUTS function in the cell division cycle will provide insight into the control and regulation of cell proliferation. In cancer, cells divide and proliferate in an uncontrolled manner. Thus, the investigation of the molecules that control cell division may lead to information needed to understand cancer cell development and growth. This project is designed to study the function of a protein called PNUTS which is proposed to be an activator of cell proliferation in breast cancer.