Determining the mechanisms that allow neoplastic cells to undergo uncontrolled proliferation is crucial to understanding carcinogenesis. Several recent studies indicate that protein phosphatases, like protein kinases, play important and specific roles in cell-cycle regulation; thus alterations in the expression or regulation of these proteins may affect cell-cycle progression and could even allow cells to undergo unregulated proliferation. A role for protein phosphatases in the tumor promotion process has also emerged from studies with okadaic acid, microcystin-LR, and calyculin A, three highly specific and potent inhibitors of certain serine/threonine protein phosphatases (PPases) that have tumor promoting activity. We have cloned and characterized three human PPases, and one, designated PP5, is particularly attractive for further studies. PP5 is potently inhibited by okadaic acid and calyculin A, two potent tumor promoters in mouse skin. However, unlike the other known PPases, which are expressed at constant levels, PP5 expression is high during log phase growth and low or undetectable in quiescent or differentiated cell cultures. The expression of PP5 is induced by the addition of serum and/or 17beta-estradiol in some cell types, and the inhibition of PP5 expression enhances the ability of both the p53 tumor suppressor protein and dexamethasone, a synthetic glucocorticoid agonist, to induce the expression of the p21 cyclin- dependent kinase inhibitor protein in A549 cells. Together these studies suggest that PP5 plays an important role in the regulation G1/S- phase transition. This proposal is designed to test the hypothesis that protein phosphatases play an important role in cell cycle progression; thus, the interference of their activity may contribute to the aberrant proliferative behavior of neoplastic cells. These studies will focus on the following specific aims:
Aim 1. Further characterize the roles of PP5 in the normal and aberrant control of cell cycle progression.
Aim 2. Characterize the relationship of PP5 in glucocorticoid mediated inhibition of cell growth and """"""""cross talk"""""""" between signaling networks induced by hormones and growth factors.
Aim 3. Characterize the mechanisms regulating the expression of PP5. Through these studies we hope to further characterize the role of protein phosphatases in the regulation of cell cycle and gain insight into the how protein phosphatases may be involved in the aberrant proliferation of neoplastic cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Poland, Alan P
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University of South Alabama
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Choy, Meng S; Swingle, Mark; D'Arcy, Brandon et al. (2017) PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors. J Am Chem Soc 139:17703-17706
Mazalouskas, Matthew D; Godoy-Ruiz, Raquel; Weber, David J et al. (2014) Small G proteins Rac1 and Ras regulate serine/threonine protein phosphatase 5 (PP5)·extracellular signal-regulated kinase (ERK) complexes involved in the feedback regulation of Raf1. J Biol Chem 289:4219-32
Swingle, Mark R; Honkanen, Richard E (2014) Development and validation of a robust and sensitive assay for the discovery of selective inhibitors for serine/threonine protein phosphatases PP1? (PPP1C) and PP5 (PPP5C). Assay Drug Dev Technol 12:481-96
Ortsäter, Henrik; Grankvist, Nina; Honkanen, Richard E et al. (2014) Protein phosphatases in pancreatic islets. J Endocrinol 221:R121-44
Theobald, Benjamin; Bonness, Kathy; Musiyenko, Alla et al. (2013) Suppression of Ser/Thr phosphatase 4 (PP4C/PPP4C) mimics a novel post-mitotic action of fostriecin, producing mitotic slippage followed by tetraploid cell death. Mol Cancer Res 11:845-55
Mitra, A; Menezes, M E; Pannell, L K et al. (2012) DNAJB6 chaperones PP2A mediated dephosphorylation of GSK3? to downregulate ?-catenin transcription target, osteopontin. Oncogene 31:4472-83
Skarra, Dana V; Goudreault, Marilyn; Choi, Hyungwon et al. (2011) Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5. Proteomics 11:1508-16
Amable, Lauren; Grankvist, Nina; Largen, Jason W et al. (2011) Disruption of serine/threonine protein phosphatase 5 (PP5:PPP5c) in mice reveals a novel role for PP5 in the regulation of ultraviolet light-induced phosphorylation of serine/threonine protein kinase Chk1 (CHEK1). J Biol Chem 286:40413-22
Burke, Christopher P; Swingle, Mark R; Honkanen, Richard E et al. (2010) Total synthesis and evaluation of phostriecin and key structural analogues. J Org Chem 75:7505-13
Swingle, Mark R; Amable, Lauren; Lawhorn, Brian G et al. (2009) Structure-activity relationship studies of fostriecin, cytostatin, and key analogs, with PP1, PP2A, PP5, and( beta12-beta13)-chimeras (PP1/PP2A and PP5/PP2A), provide further insight into the inhibitory actions of fostriecin family inhibitors. J Pharmacol Exp Ther 331:45-53

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