Co-regulator mechanisms in lung cancer
Abstracts
Initial Award Abstract |
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Lung cancer is the most common lethal cancer in the United States, with smoking responsible for over 85% of all cases. The cause of smoking-induced lung cancer is thought to involve stepwise mutations in genes that promote and/or inhibit cancer growth. Many of these genes have been discovered, but others remain to be found and their function in the lung defined. Understanding the mechanisms involved in regulating proliferation and differentiation of bronchial epithelial cells is important for further understanding the causes, diagnosis and treatment of lung cancer.
We have recently identified a new protein called LMO-4, a member of a family of proteins that participate in gene regulation. Proteins belonging to this group have been shown to cause leukemia. We were therefore intrigued to find that LMO-4 is highly abundant in bronchial epithelial cells when these cells are proliferating. In addition, we have found that LMO-4 can associate with another protein, Trip230, which has been shown to bind to the retinoblastoma protein. Abnormalities in the retinoblastoma protein, which normally inhibits cell proliferation, have been implicated in the progression of lung cancer. Our hypothesis is therefore that LMO-4 is involved in regulation of proliferation of lung epithelial cells in normal lung and in lung cancer.
To test this hypothesis, we plan to carefully study where LMO-4 and Trip230 are expressed in the lung both during normal development and in cancers. We will characterize the LMO-4/Trip230 interaction in test tubes and determine whether these proteins can be found in association in lung cancer cells. Finally, we will test the effect of LMO-4 on proliferation and tumorigenic potential of lung cancer cells.
With our work, we hope to gain new insights into how smoking causes lung cancer and define genes and proteins that could potentially lead to new ideas about treatment of smoking-induced lung cancer. |
Final Report |
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Lung cancer is the most common lethal cancer in the Unified States, with smoking responsible for over 85% of all cases. The cause of smoking-induced lung cancer is thought to involve stepwise mutations in genes that promote and/or inhibit cancer growth Many of these genes have been discovered, but others remain to be found and their function in the lung defined. Understanding the mechanisms involved in regulating proliferation and differentiation of bronchial epithelial cells is important for further understanding the cause, diagnosis and treatment of lung cancer.
Abnormal behavior of malignant cells is stems from altered expression of genes responsible for controlling cellular proliferation and maturation. To gain insight into this process, we have focused on discovering proteins that regulate gene expression in respiratory and other epithelial cells. Currently, we are characterizing two distinct transcriptional pathways that may be important for growth and differentiation control in epithelial cells.
The first pathway centers on a recently discovered gene regulatory protein called LMO-4. Because LMO-4 is highly related to oncogenes causing leukemia, we have proposed that it plays a role in regulation of lung epithelial cells in the 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. 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 fuit 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. Our current work focuses on understanding the role of the LMO-4 and NTF-1 genes in epithelial cells.
Cells of the upper respiratory track are characterized by the expression of structural proteins referred to as keratins that provide mechanical strength to the epithelium. In smoking-induced cancer of the respiratory epithelium the expression of keratin genes is altered. The second pathway we are investigating is involved in regulating one of these keratin genes, keratin 14. Using gene transfer studies into human epithelial cells, we have discovered that the co-activator proteins CREB binding proteins and p300 activate the keratin 14 gene and that interference with the activity of these co-activators by POU transcription factors can repress expression of the keratin 14 gene. Since the CREB binding protein and p300 have been linked to growth control, our studies provide insight into the mechanisms of how growth and maturation of epithelial cells can be coordinated.
In our future studies we plan to directly test the importance of these transcriptional mechanisms in growth regulation of bronchial and other epithelial cells. Our hope is to understand how these gene-regulatory pathways 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. |
