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Transcriptional regulation in normal and neoplastic lung

Institution: University of California, San Diego
Investigator(s): Elena Kudryavtseva, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9FT-0216 Award: $69,350
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
The primary cause of lung cancer is smoking. Presumably, tobacco smoking changes the expression or function of several genes that regulate growth of epithelial cells in the respiratory tract. While we know the identity of many genes involved in this process, it is likely that several genes important for lung carcinogenesis remain to be discovered. Lessons from the study of organ development suggest that many genes important for normal development, even in simple organisms such as the fruit fly, often play roles in cancer formation. Consequently, one approach to identify novel genes significant for the formation of lung cancer is to search and test the function of genes that have been shown to play crucial roles in normal development.

We are studying the role of a protein called LMO-4 that is involved in gene regulation. Because LMO-4 is highly related to oncogenes causing leukemia, we have proposed that it plays a role in the regulation of lung epithelial cells in normal lung and in lung cancer. Recently, we have isolated a new gene that encodes a protein that associates with LMO-4. This gene, NTF-1, corresponds to a gene that is required for the formation of the cuticle and trachea in fruit flies. We propose to test the function of this new gene in mammalian lung formation and in lung cancer.

We already know that, besides low level expression of NTF-1 in the brain, this gene is selectively expressed in epithelial cells, including those of internal epithelia such as in the developing lung. Based on the importance of NTF-1 in formation of epithelial tissues in fruit flies, we propose that the mammalian NTF-1 gene plays similar critical functions in epithelial cells of the lung. Further, we suggest that subversion of the function or expression of NTF-1 may play a role in lung cancer.

To test this idea, we plan to carefully study where NTF-1 is expressed in the lung both during normal lung development and in lung cancers. To test the function of the mammalian NTF-1 gene more definitively, we propose to disrupt the gene in animal models and examine changes in the lungs and other epithelial tissues.

These experiments may lead to insights into how normal and cancerous lung tissue forms. Our hope is to identify one or more of the molecules and pathways that contribute to lung cancer formation in response to smoking. In the long-term, these studies may also provide ideas for new treatments of lung cancer.
Publications

The POU domain factor skin-1a represses the keratin 14 promoter independent of DNA binding: possible role for interactions between skn-1a and CBP/p300
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Sugihara TM, Kudryavtseva EI, Kumar V, Horridge JJ, and Andersen B ART
Yr: 2001 Vol: 276 Nbr: Abs: Pg: 33036 - 33044

Identification and characterization of a novel LMO-4-interacting protein, mammalian grainyhead-like epithelial transactivator (GET-1).
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Kudryavtseva EI, Sugihara TM, Wang N, Lasso RJ, Gudnason JF Lipkin SM and Andersen B ART
Yr: 0 Vol: Nbr: Abs: Pg: