The goal of the proposed experiments is to determine how the serine/threonine kinase Pak4 functions in the regulation of cell growth and transformation. Pak4 is an effector of the Rho GTPases Cdc42 and Rac, and was originally identified as a protein that functions in cytoskeletal organization. More recently, Pak4 was also shown to have important roles in controlling cell growth and survival. Pak4 is overexpressed in cancer cell lines, and Pak4 is highly transforming in established immortalized cell lines. In contrast, in primary cells Pak4 has a completely different function and triggers premature senescence rather than increased growth. In both respects Pak4 is similar to strong oncogenes such as oncogenic Ras, which are highly transforming in immortalized cells but inhibit growth in primary cells. Studying the role for Pak4 in cell growth is very important for understanding how Pak4 and Rho GTPases are associated with oncogenic transformation. The experiments in this proposal will take advantage of Pak4 null fibroblasts that have been generated in our lab, in order to study Pak4's role in the regulation of cell growth and transformation in immortalized cells, and premature senescence in primary cells. The following aims will be addressed:
Aim 1. 1. What role does Pak4 have in oncogenic transformation? Immortalized Pak4 null and control fibroblasts will be used to test the hypothesis that Pak4 is essential for transformation by Rho GTPases and their activators. We will also study the signaling pathways involved in Pak4 mediated transformation.
Aim 1. 2. What role does Pak4 have in the control of cell proliferation? The control of cell proliferation and transformation are closely associated. Here we will use the immortalized Pak4 null fibroblasts to test the hypothesis that Pak4 is required for cell cycle entry and proliferation in response to Rho GTPases. We will also determine whether cell cycle regulatory proteins function downstream to Pak4 during cell cycle progression.
Aim 2. What signaling pathways mediate Pak4 induced premature senescence in primary cells? We will first test the hypothesis that Pak4 induced senescence in primary ceils is mediated by the ERK MAP Kinase, leading to induction of cell cycle regulatory proteins and subsequent inhibition of cell growth. We will also test the hypothesis that cytoskeletal regulatory proteins play an important role in Pak4 induced senescence. Finally, we will also determine whether Pak4 is required for oncogene induced senescence. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076342-09
Application #
7079336
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Yassin, Rihab R,
Project Start
1998-08-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
9
Fiscal Year
2006
Total Cost
$304,521
Indirect Cost
Name
Rutgers University
Department
Biology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Nekrasova, Tanya; Minden, Audrey (2012) Role for p21-activated kinase PAK4 in development of the mammalian heart. Transgenic Res 21:797-811
Nekrasova, Tanya; Minden, Audrey (2011) PAK4 is required for regulation of the cell-cycle regulatory protein p21, and for control of cell-cycle progression. J Cell Biochem 112:1795-806
Wong, Lisa Epstein; Reynolds, Albert B; Dissanayaka, Nadishani T et al. (2010) p120-catenin is a binding partner and substrate for Group B Pak kinases. J Cell Biochem 110:1244-54
Liu, Y; Chen, N; Cui, X et al. (2010) The protein kinase Pak4 disrupts mammary acinar architecture and promotes mammary tumorigenesis. Oncogene 29:5883-94
Tian, Yanmei; Lei, Liang; Cammarano, Marta et al. (2009) Essential role for the Pak4 protein kinase in extraembryonic tissue development and vessel formation. Mech Dev 126:710-20
Liu, Yingying; Xiao, Hang; Tian, Yanmei et al. (2008) The pak4 protein kinase plays a key role in cell survival and tumorigenesis in athymic mice. Mol Cancer Res 6:1215-24
Cammarano, Marta S; Nekrasova, Tanya; Noel, Beatrice et al. (2005) Pak4 induces premature senescence via a pathway requiring p16INK4/p19ARF and mitogen-activated protein kinase signaling. Mol Cell Biol 25:9532-42
Li, Xiaofan; Minden, Audrey (2005) PAK4 functions in tumor necrosis factor (TNF) alpha-induced survival pathways by facilitating TRADD binding to the TNF receptor. J Biol Chem 280:41192-200
Gnesutta, Nerina; Minden, Audrey (2003) Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4. Mol Cell Biol 23:7838-48
Qu, Jian; Li, Xiaofan; Novitch, Bennet G et al. (2003) PAK4 kinase is essential for embryonic viability and for proper neuronal development. Mol Cell Biol 23:7122-33

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