Although aberrant signaling through various Rac isoforms has been conceptually associated with many aspects of cancer cell biology, there,remains a significant gap in our knowledge on the mechanism of contribution by Rac GTPases to cancer development. To date few animal models are available to directly study the involvement of Rac GTPases in cancer in vivo. Limited information obtained from human cancer specimen screening suggest that upregulation of expression or activity, but rarely mutation, of Rac GTPases are associated with a wide spectrum of human tumors, raising the possibility that Rac might serve as signal modifier or mediator of primary genetic or mitogenic "hits" in tumor induction and progression. The p53 tumor suppressor pathway, on the other hand, constitutes a check point in cell cycle progression that is responsive to proliferative signals normally required for cell growth. Disruption of p53 leads to lymphomagenesis in mice, and loss of gene function in p53 pathway is a common feature in many human cancers, including Burkitt's lymphoma. Our preliminary studies demonstrating that Rac activities are inversely regulated by p53 functional expression and are required for the p53 controlled cell growth or transformation in primary MEFs and murine lymphocytes/lymphoma lead to the central hypothesis of this proposal that Rac GTPase signaling constitutes a novel target in p53 deficiency-mediated tumorigenesis. This hypothesis is further supported by the observation that Rac activities are inversely regulated by the p53 functional status of human Burkitt's lymphoma cells that carries c-myc and p53 defects and are required for the proliferation phenotype of the tumor cells. In addition, by structure-function based rational design we have developed a Rac-specific small molecule inhibitor that is effective in suppressing Rac activity in lymphoid and lymphoma cells and other tumor cells. Thus we propose three specific aims to implicate Rac GTPases as useful targets in p53 deficiency-mediated lymphomagenesis. (1) To define the role of individual Rac GTPases by using Rac1, Rac2, and/or Rac3 knockout hematopoietic stem/progenitor cells in the p53-/- or the Eu-myc/p53+/- genetic background in a bone-marrow transplantation protocol. (2) To analyze the effectiveness of a Rac-specific small molecule inhibitor, NSC23766, in preventing p53 deficiency-induced lymphomagenesis in mice. (3) To apply the Rac targeting strategy established in the murine lymphoma model to the studies of p53 deficient human Burkitt's lymphoma cells. The goals of these studies are to implicate the functional connection between the p53 tumor suppressor and Rac GTPase signaling pathways in p53 deficient mouse and human lymphoma models and to validate Rac signaling as a useful anti-cancer target. The results are likely relevant to future design of targeted therapies toward a variety of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125658-05
Application #
8018514
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Howcroft, Thomas K
Project Start
2007-02-10
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$276,450
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Akbar, Huzoor; Shang, Xun; Perveen, Rehana et al. (2011) Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation. PLoS One 6:e22117
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Bosco, Emily E; Ni, Wenjun; Wang, Lei et al. (2010) Rac1 targeting suppresses p53 deficiency-mediated lymphomagenesis. Blood 115:3320-8
Bosco, E E; Nakai, Y; Hennigan, R F et al. (2010) NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation. Oncogene 29:2540-9
Kalfa, Theodosia A; Pushkaran, Suvarnamala; Zhang, Xiaoling et al. (2010) Rac1 and Rac2 GTPases are necessary for early erythropoietic expansion in the bone marrow but not in the spleen. Haematologica 95:27-35
Guo, Fukun; Cancelas, Jose A; Hildeman, David et al. (2008) Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood 112:1767-75