Aberrant cell proliferation and differentiation following toxic injury to bronchial epithelium can lead to the development of various respiratory diseases including lung cancer, but the underlying molecular mechanisms involved in such processes remain enigmatic. The proposed research is based on the premise that AP-1 family of transcriptional factors act as environmental biosensors to various external toxic stimuli and regulate genes involved in cell proliferation and differentiation. Recently we have shown that Fra-1 (fos-related transcription factor-1), a member AP-1 family, up regulates the gene expression involved in airway squamous metaplasia, a preneoplastic lesion. Other studies have demonstrated a protracted expression of Fra-1 in response to silica and asbestos exposure, which causes bronchial epithelial cell transformation. Furthermore, we have observed that Fra-1 expression is induced by phorbol ester PMA and tobacco smoke in airway epithelial cells both in vitro and in vivo. Therefore, we hypothesize that protracted induction of Fra-1 expression by toxicants compromises the normal bronchial epithelial cell growth and differentiation thereby altering pulmonary defense and injury-repair processes, which culminate in cellular transformation. The proposed Specific Aims to test the above hypothesis are to: 1) Define the promoter cis-acting elements and trans-acting factors that regulate PMA and tobacco smoke-inducible Fra-1 expression by in vivo footprinting, deletion/mutation and electrophoretic mobility shift assays. 2) Elucidate the signal transduction pathways that mediate PMA- and tobacco smoke-inducible fra1 expression employing pharmacological inhibitors as well as genetic mutants of various mitogen-activated protein kinases; and 3) Examine the functional role of Fra-1 in PMA- and tobacco smoke-induced bronchial epithelial injury-repair and transformation. To achieve these objectives, we will use two independent, but complementary approaches that utilize in vitro cell culture and in vivo transgenic mouse models that over express wild type or dominant negative-mutant Fra-1, specifically in bronchial epithelial cells. These studies should provide additional insight into mechanisms of toxicant-inducible gene expression and also establish the specific role for Fra-1 in lung biology and toxicant-induced respiratory pathogenesis. Also, these results should enable us to identify lung-specific Fra-1-inducible genes that might offer unique opportunity to use them as potential diagnostic markers or drug targets for early detection and prevention of respiratory pathogenesis.
| Elangovan, Indira M; Vaz, Michelle; Tamatam, Chandramohan R et al. (2018) FOSL1 Promotes Kras-induced Lung Cancer through Amphiregulin and Cell Survival Gene Regulation. Am J Respir Cell Mol Biol 58:625-635 |
| Potteti, Haranatha R; Rajasekaran, Subbiah; Rajamohan, Senthilkumar B et al. (2016) Sirtuin 1 Promotes Hyperoxia-Induced Lung Epithelial Cell Death Independent of NF-E2-Related Factor 2 Activation. Am J Respir Cell Mol Biol 54:697-706 |
| Mishra, Rakesh K; Potteti, Haranatha R; Tamatam, Chandramohan R et al. (2016) c-Jun Is Required for Nuclear Factor-?B-Dependent, LPS-Stimulated Fos-Related Antigen-1 Transcription in Alveolar Macrophages. Am J Respir Cell Mol Biol 55:667-674 |
| Reddy, Narsa M; Potteti, Haranatha R; Vegiraju, Suryanarayana et al. (2015) PI3K-AKT Signaling via Nrf2 Protects against Hyperoxia-Induced Acute Lung Injury, but Promotes Inflammation Post-Injury Independent of Nrf2 in Mice. PLoS One 10:e0129676 |
| Rajasekaran, Subbiah; Tamatam, Chandramohan R; Potteti, Haranatha R et al. (2015) Visualization of Fra-1/AP-1 activation during LPS-induced inflammatory lung injury using fluorescence optical imaging. Am J Physiol Lung Cell Mol Physiol 309:L414-24 |
| Jain, Atul D; Potteti, Haranatha; Richardson, Benjamin G et al. (2015) Probing the structural requirements of non-electrophilic naphthalene-based Nrf2 activators. Eur J Med Chem 103:252-68 |
| Vaz, Michelle; Rajasekaran, Subbiah; Potteti, Haranatha R et al. (2015) Myeloid-specific Fos-related antigen-1 regulates cigarette smoke-induced lung inflammation, not emphysema, in mice. Am J Respir Cell Mol Biol 53:125-34 |
| Reddy, Sekhar P; Natarajan, Viswanathan; Dudek, Arkadiusz Z (2014) MARCKS is marked in combating lung cancer growth and acquired resistance. Am J Respir Crit Care Med 190:1084-6 |
| Mittal, Manish; Siddiqui, Mohammad Rizwan; Tran, Khiem et al. (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20:1126-67 |
| Mezu-Ndubuisi, Olachi J; Wanek, Justin; Chau, Felix Y et al. (2014) Correspondence of retinal thinning and vasculopathy in mice with oxygen-induced retinopathy. Exp Eye Res 122:119-22 |
Showing the most recent 10 out of 48 publications
