Transcription factor modification: A role in lung cancer?

Institution:	California Institute of Technology
Investigator(s):	Hwan-Ching Tai, B.S.
Award Cycle:	2004 (Cycle 13)	Grant #: 13DT-0065	Award: $6,097
Subject Area:	Cancer
Award Type:	Dissertation Awards

Abstracts

Initial Award Abstract

The subjects of this study are two proteins called c-Fos and c-Jun, which have important roles in the development of lung cancer induced by cigarette smoke. When the airway lining is exposed to toxicants in the cigarette smoke, c-Fos and c-Jun are activated in certain cells. c-Fos and c-Jun function as a pair by forming a plier-like structure that clamps down on DNA and turns on particular genes. Activation of these genes can lead a cell down the path toward cancer. Many studies suggest that c-Fos and c-Jun induce lung cancer, while others suggest they may suppress it. The reasons why they can act in both ways are not yet clear, and understanding why will be important for controlling their functions. We have hypothesized that the dual nature of c-Fos and c-Jun is due to certain chemical modifications that alter their properties. The goal of our studies is to determine whether a type of small sugar is linked to them, and, if so, how this sugar affects their functions in lung cancer.

Chemical modifications change protein functions by adding small tags to them so they will be recognized differently by other molecules in the cell. The tagging process is reversible and its effect can be further controlled by another tag. It is analogous to painting a taxi yellow so people will wave at it, but putting on the “off-duty” light will prompt them to wait for the next cab. The cell uses these tags to quickly generate multiple functions out of the same protein. A type of tag called phosphate at certain positions of c-Fos and c-Jun appears to be necessary for their ability to induce cancers. However, c-Fos and c-Jun tagged at these same positions are also reported to suppress tumors. These perplexing findings suggest to us there may be additional unidentified tags that also control their activities. In fact, preliminary studies in our laboratory have identified a new tag on c-Fos and c-Jun, called O-linked N-acetylglucosamine, which is a small sugar molecule. This sugar tag generally modulates the function of a protein in a manner opposite to the phosphate tag. Since phosphate tags appear to be necessary for the cancer-inducing effects of c-Fos and c-Jun, we will investigate if the sugar tag has tumor-suppressive effects in lung cancer cells. The proposed research will provide insights into the mechanism that cigarette smoke induces lung cancer, as well as new drug targets for lung cancer therapy.

Publications

Parallel identification of O-GlcNAc modified proteins from cell lysates.
Periodical: Journal American Chemicaal Society			Index Medicus:
Authors: Tai HC, Khidekel N, Ficarro SB, Peters EC, Hsieh-Wilson LC				ART
Yr: 2004	Vol: 126	Nbr:	Abs:	Pg: 10500-10501

Parallel identification of O-GlcNAc modified proteins from cell lysates.
Periodical: Journal American Chemicaal Society			Index Medicus:
Authors: Tai HC, Khidekel N, Ficarro SB, Peters EC, Hsieh-Wilson LC				ART
Yr: 2004	Vol: 126	Nbr:	Abs:	Pg: 10500-10501