This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Serine/threonine phosphatase 5 (PP5) is an enzyme that has an emerging role in the regulation of signal transduction and altered PP5 activity appears to contribute to tumor development and maintenance. While protein kinase enzymes catalyze the transfer of a phosphate group from a donor to an acceptor protein in various signaling pathways, protein phosphatases, in turn, reverse the action of kinases by removing a phosphate. PP5 belongs to the PPP-family of enzymes, which also includes PPI and PP2A. Both genetic studies and studies using inhibitors of protein phosphatases (e.g. okadaic acid) indicate protein phosphatases play an important role(s) in the regulation of cell cycle progression and processes implicated in tumor promotion. PP5 has been shown to play a negative regulatory role in a p53-mediated signaling cascade leading to the induction of a cyclin-dependent kinase inhibitor protein (p21WAFI/Cipl) and Gl/S-phase growth arrest. The expression of PP5 is also responsive to 17- beta estradiol and hypoxia inducible factor-l (HIF-l), which are both positive factors in the development of human breast cancer. In addition, the constitutive over expression of PP5 promotes cell survival during oxidative stress (an issue in cardiovascular disease and in developing tumors) and converts MCF-7 breast cancer cells from an estrogen-dependent into an estrogen-independent phenotype. Recently, increased PP5 expression has been shown by tumor microarray to have a positive correlation with breast cancer. The studies described in this proposal are designed to test the hypothesis that PP5 plays an important role in the regulation of cellular responses to hypoxic stress, and that changes in the normal biological functions of PP5 may contribute to the development of cancer. These studies will expose undergraduates to research on cancer in a form that is easy to understand (the on-off type roles of signaling pathways) and also expose them to tissue culture as well as basic cell/molecular biology techniques.
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