Ovarian cancer is identified as the fifth leading cause of cancer death in the United States with approximately 16,000 deaths every year. Although major advances have been made in understanding the pathology of this disease, 52 % of patients die because of the aggressive growth of these cancers. It has been recently observed that the lipid growth factor lysophosphatidic acid (LPA) promotes ovarian cancer genesis and progression. Our recent studies have shown that LPA-mediated oncogenic signaling involves the gep oncogenes, defined by the activated mutants of G?12 and G?13, that differentially regulate a number of MAP kinases including Jun N-terminal kinase (JNK). These MAPKs, in turn, elicit a multitude of cellular responses required for different physiological stimuli. The signaling complexity and precision of G?12/13 indicates the possible involvement of a scaffolding protein that can modulate specific signaling responses. Recently we have shown that these gep oncogenes, upon stimulation with LPA, interact with a scaffolding protein involved in the activation of JNKs (Kashef et al., 2005). This novel scaffolding protein known as JNK-interacting Leucine- zipper Protein (JLP) potentiates the activation of JNK by G?12/13. In addition, our studies indicate that JLP also tethers ?-PIX, a Rac/CDC42-specific guanine nucleotide exchange factor, to G?12/13 through which the JNK-module can be activated. Based on these results, we hypothesize that G?12/13-JLP interaction is critically involved in G?12/13-mediated activation of diverse cellular responses. In this application, we propose to test this hypothesis under the following specific aims:
Aim 1 : Characterization of G?13-JLP-?-PIX interaction through site-directed mutagenesis;
Aim 2 : Analysis of the interrelationship of G?13, JLP, and ?-PIX in forming a signaling complex;
Aim 3 : Defining the role of JLP on the oncogenic activity of G?12/13 and Aim 4: defining the Role of JLP- G?12/13 signaling in ovarian cancer genesis and progression. In addition to characterizing the etiological factors involved in the progression of ovarian cancer, the outcome of these studies is expected to identify novel therapeutic targets for the treatment of the disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Knowlton, John R
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University of Oklahoma Health Sciences Center
Anatomy/Cell Biology
Schools of Medicine
Oklahoma City
United States
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Ha, Ji Hee; Radhakrishnan, Rangasudhagar; Jayaraman, Muralidharan et al. (2018) LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response. Cancer Res 78:1923-1934
Dhanasekaran, Danny N; Reddy, E Premkumar (2017) JNK-signaling: A multiplexing hub in programmed cell death. Genes Cancer 8:682-694
Ha, Ji Hee; Ward, Jeremy D; Radhakrishnan, Rangasudhagar et al. (2016) Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via G?i2, Src, and HIF1? signaling nexus. Oncotarget 7:37664-37679
Ha, Ji Hee; Yan, Mingda; Gomathinayagam, Rohini et al. (2016) Aberrant expression of JNK-associated leucine-zipper protein, JLP, promotes accelerated growth of ovarian cancer. Oncotarget 7:72845-72859
Ward, Jeremy D; Ha, Ji Hee; Jayaraman, Muralidharan et al. (2015) LPA-mediated migration of ovarian cancer cells involves translocalization of G?i2 to invadopodia and association with Src and ?-pix. Cancer Lett 356:382-91
Ha, Ji Hee; Gomathinayagam, Rohini; Yan, Mingda et al. (2015) Determinant role for the gep oncogenes, G?12/13, in ovarian cancer cell proliferation and xenograft tumor growth. Genes Cancer 6:356-364
Ha, Ji Hee; Ward, Jeremy D; Varadarajalu, Lakshmi et al. (2014) The gep proto-oncogene G?12 mediates LPA-stimulated activation of CREB in ovarian cancer cells. Cell Signal 26:122-32
Gomathinayagam, Rohini; Muralidharan, Jayaraman; Ha, Ji Hee et al. (2014) Hax-1 is required for Rac1-Cortactin interaction and ovarian carcinoma cell migration. Genes Cancer 5:84-99
Gardner, Jacob A; Ha, Ji Hee; Jayaraman, Muralidharan et al. (2013) The gep proto-oncogene G?13 mediates lysophosphatidic acid-mediated migration of pancreatic cancer cells. Pancreas 42:819-28
Kashef, Kimia; Radhakrishnan, Rangasudhagar; Lee, Clement M et al. (2011) Neoplastic transformation induced by the gep oncogenes involves the scaffold protein JNK-interacting leucine zipper protein. Neoplasia 13:358-64

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