Analysis of a lung tumor supressor gene at 3p21.3
Initial Award Abstract
Lung cancers are strongly associated with cigarette smoking. In order to understand how cigarette smoke components cause lung cancer and other smoking-related cancers, it is necessary to understand the sequence of molecular events that leads to formation of a tumor many years or decades later. According to current thinking, a number of genes need to be mutated or functionally disabled before a normal cell loses all normal growth control mechanisms and is brought onto a path of uncontrolled cell division eventually leading to a tumor. Gene mutation or inactivation has been found in genes such as p53, ras, and p16 at a relatively high frequency in human lung tumors.
However, the most common and earliest genetic change in the development of lung tumors has been mapped to the short arm of chromosome 3, in an area designated as 3p21.3. At this location, a specific chromosomal area is often deleted in lung cancer, and sometimes even both copies of this chromosomal material are lost. This phenomenon usually points to the existence of a tumor suppressor gene, which needs to be lost or inactivated completely in order for a tumor to arise.
We have cloned a new gene (named RASSF1) from the common chromosomal deletion area of chromosome 3p21.3 in lung tumors. The gene product has 50% homology to one other protein that interacts with the ras oncogene product. We do not know much about the function of this gene yet, except the following: 1) It is inactivated in a high percentage of human lung cancers (up to 80% of small cell carcinomas). 2) It suppresses cell growth and tumor formation when put back into lung cancer cells.
We will investigate further how the RASSF1 gene is inactivated in different types of lung cancers and in head and neck tumors. We will try to define its biochemical function in the cell. Finally, in order to test its presumed function as a tumor suppressor, we will delete this gene in the mouse and see if these mice develop cancer.
The study should increase our understanding of the mechanisms of lung cancer initiation. If the causes of smoking-associated cancers are better understood at the molecular level, more efficient early screening procedures and future gene therapy approaches may be developed. |