The role of hCDC4 regulation of cyclin E in lung cancer
Abstracts
Initial Award Abstract |
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In cancer development (tumorigenesis) the molecular mechanisms that regulate cell division become altered, such that “brakes” on these events are bypassed and division can proceed in the face of genetic mutations that would otherwise stimulate normal cells to stop. Recently, a cell cycle regulatory protein, called cyclin E, has emerged as a “key player” in tumor progression. Thus, there is much interest in any additional factors that might influence the stability or expression of cyclin E. This study will investigate the cell division role of a newly identified gene, called hCDC4, which encodes a protein that functions in proteolysis (i.e., protein degradation). It has become established that numerous proteolytic processes involved in regulating cell division are defective in lung tumors. It is likely that hCDC4 regulates the proteolysis of cyclin E. In normal cells, cyclin E protein is unstable and its levels decline rapidly once DNA synthesis begins. The drop in cyclin E protein levels is mediated by hCDC4, which binds to cyclin E and "tags" it for proteolysis. In many lung tumors, however, cyclin E protein levels are elevated and present at inappropriate times during cell division, which is associated with poor prognosis. This "deregulated" expression of cyclin E has been shown experimentally to cause tumors in mice and induce chromosome abnormalities in cultured cells.
This research focuses on whether alteration of hCDC4 is responsible for the aberrant regulation of cyclin E protein observed in lung tumors. Our preliminary evidence that will be explored in more detail include: (1) in most lung tumors, deregulated cyclin E protein cannot be explained by differences in gene expression; (2) the hCDC4 gene is located on a region of the genome that is deleted in nearly half of all lung tumors; and (3) preliminary analysis has detected a hCDC4 gene mutation in a lung tumor cell line. These studies will also attempt to define the molecular mechanism by which deregulated cyclin E contributes to the generation of chromosome abnormalities and possibly other forms of genetic damage in cancer.
Our aim is to better understand the proteolytic regulation of cyclin E and how alteration of this process contributes to lung tumorigenesis. This knowledge could ultimately aid in the formulation of rational management strategies for the disease. |
