The proposed study intends to elucidate signal transduction mechanisms that establish molecular hierarchies in response to hypoxic challenges in salivary epithelial cells. Our current studies on the characterization of salivary signal transduction pathways have led to the identification of a novel non-receptor tyrosine kinase, Etk/BMX, expressed in rat parotid glands and rat salivary Pa-4 epithelial cells. We demonstrated that the paracellular barrier function and hypoxia-response element (HRE)-dependent gene expression could be enhanced upon the activation of Etk in salivary Pa-4 cells. In this application, we will test the hypothesis that Etk modulates the interplay between tight junctional component(s) and its interacting protein(s) for the maintenance of epithelial integrity under hypoxic condition. We will also test the hypothesis that Etk serves as a """"""""molecular switch"""""""" to activate the HRE-dependent transcription, thereby providing cells the capacity to survive prolonged hypoxia. The long-term goal of this research is to use Etk-mediated cellular and biochemical modulations and gene regulation in salivary Pa-4 cells as a paradigm to elucidate mechanistic hierarchies in which the activation of a signaling pathway directs the adaptive responses to environmental stress. The proposed study is of great significance as the dysregulation of signaling pathway and/or hypoxia responses is associated with many human diseases, such as ischemic reperfusion and salivary tumors. There are four Specific Aims in this application: (i) To establish the role of Etk-dependent phosphorylation in salivary epithelial tight junction assembly/disassembly under hypoxia; (ii) To establish the mechanism by which Etk promotes tight junction assembly and enhances salivary epithelial barrier functions under normoxia and hypoxia; (iii) To determine whether Etk activation is essential for modulating salivary epithelial hypoxia-induced gene expression; and (iv) To verify and characterize selected Etk activation-induced target genes, which mediate adaptive responses to prolonged hypoxic exposure in salivary epithelial cells. These results will provide a new dimension to the Etk-mediated signaling pathways and mechanisms in salivary epithelial adaptive responses to hypoxia. A better knowledge of the molecular basis of Etk-activation and its effect on cellular, biochemical and genomic events under (patho) physiological conditions is key to successful future tissue engineering and drug discovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014183-02
Application #
6516676
Study Section
Special Emphasis Panel (ZRG1-OBM-2 (02))
Program Officer
Kousvelari, Eleni
Project Start
2001-07-01
Project End
2006-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
2
Fiscal Year
2002
Total Cost
$292,500
Indirect Cost
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Cheng, Chun-Ting; Kuo, Ching-Ying; Ouyang, Ching et al. (2016) Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells. Cancer Res 76:5006-18
Kuo, Ching-Ying; Cheng, Chun-Ting; Hou, Peifeng et al. (2016) HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity. Oncotarget 7:34052-69
Chen, Yun-Ru; Tsou, Brittany; Hu, Shuya et al. (2016) Autophagy induction causes a synthetic lethal sensitization to ribonucleotide reductase inhibition in breast cancer cells. Oncotarget 7:1984-99
Kuo, Ching-Ying; Li, Xu; Stark, Jeremy M et al. (2016) RNF4 regulates DNA double-strand break repair in a cell cycle-dependent manner. Cell Cycle 15:787-98
Lee, Young-Ho; Liu, Xiyong; Qiu, Fuming et al. (2015) HP1? is a biomarker for breast cancer prognosis and PARP inhibitor therapy. PLoS One 10:e0121207
Lee, Young-Ho; Ann, David K (2015) Bi-phasic expression of Heterochromatin Protein 1 (HP1) during breast cancer progression: Potential roles of HP1 and chromatin structure in tumorigenesis. J Nat Sci 1:e127
Chen, Ching-Hsien; Cheng, Chun-Ting; Yuan, Yuan et al. (2015) Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment. Oncotarget 6:15194-208
Kuo, Ching-Ying; Li, Xu; Kong, Xiang-Qian et al. (2014) An arginine-rich motif of ring finger protein 4 (RNF4) oversees the recruitment and degradation of the phosphorylated and SUMOylated Kr├╝ppel-associated box domain-associated protein 1 (KAP1)/TRIM28 protein during genotoxic stress. J Biol Chem 289:20757-72
Hou, Peifeng; Kuo, Ching-Ying; Cheng, Chun-Ting et al. (2014) Intermediary metabolite precursor dimethyl-2-ketoglutarate stabilizes hypoxia-inducible factor-1? by inhibiting prolyl-4-hydroxylase PHD2. PLoS One 9:e113865
Lin, H H; Lin, S-M; Chung, Y et al. (2014) Dynamic involvement of ATG5 in cellular stress responses. Cell Death Dis 5:e1478

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