Determining the mechanisms that allow neoplastic cells to undergo uncontrolled proliferation is crucial to understanding carcinogenesis. Recent studies have made it very clear 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. We have cloned and characterized four human PPases, and one, designated PP5, is particularly attractive for further studies. PP5 acts to suppress a glucocorticoid-induced, p53- mediated signaling cascade leading to the induction of G1/S-phase growth arrest. Studies into the mechanisms regulating PP5 activity have revealed that the expression of PP5 is responsive to 17-13 estradiol and hypoxia inducible factor-1 (HIF-1), which are both positive factors in the development of human breast cancer. Furthermore, the constitutive over expression of PP5 aids cell survival during oxidative stress and converts MCF-7 cells from an estrogen-dependent into an estrogen-independent phenotype. Thus, aberrant PP5 activity may also contribute to tumor development. This proposal is designed to test the hypothesis that protein phosphatases play an important role in cell cycle progression; thus, abnormal expression or the interference of their normal activity may contribute to the aberrant proliferative behavior of neoplastic cells. These studies will focus on the following specific aims:
Aim 1. Continue to characterize the roles played by PP5 in glucocorticoid receptor-mediated signaling networks.
Aim 2. Determine the roles of PP5 in HIF-1- and estrogen-mediated signaling cascades that aid cell survival and in cross-talk between p53-, GR- and HIF-1-mediated signaling networks.
Aim 3. Determine if PP5 expression is a positive factor in the development of human breast cancer, and characterize the physiological role for PP5 through the development of PP5-knockout and PP5-loxP transgenic mice. Through these studies we hope to further characterize the role of protein phosphatases in the regulation of cell cycle control and gain insight into the how protein phosphatases may be involved in the aberrant proliferation of neoplastic cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA060750-12
Application #
6872168
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Yang, Shen K
Project Start
1994-01-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
12
Fiscal Year
2005
Total Cost
$262,800
Indirect Cost
Name
University of South Alabama
Department
Biochemistry
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
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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