Molecular mechanisms of cellular immortalization and cancers

The research focus of our laboratory is on the molecular mechanisms of tumorigenesis. Specifically, we are interested in cellular senescence and immortalization and their roles in tumorigenesis. Normal human cells undergo about 50 divisions before senescing or ceasing proliferation. Cancer cells, in contrast, divide without limitation and are immortal. Therefore, replicative senescence is thought to be both a tumor suppression mechanism and a contributor to organismic aging. Our long-term goal is to understand how normal cells become immortal cancerous cells.

Specialized DNA sequences called telomeres are found at the ends of chromosomes in the cells and appear to control the transition to immortality. Normal cells are unable to elongate telomeres and their telomeres shorten as they proliferate. Therefore, the length of telomeres determines the life span of a normal cell. However, cancer cells can elongate their telomeres by either telomerase-dependent or independent mechanisms. Genes that participate in the telomere maintenance are thus likely to play an important role in the progression of many types of cancer. Using a retrovirus proviral tagging approach, we are currently carrying out a genetic screen to identify the immortalization genes in a human cell culture model. These genes are potential diagnostic markers for cancer and targets of therapeutic intervention.

The other aspect of our research interest is cellular senescence. Senescence can be induced prematurely in normal cells by oncogenic activation of signaling pathways. One of the common features of all senescence is the involvement of the p16Ink4a/pRb tumor-suppressing pathway. p16Ink4a is one of the key links between cellular senescence and cell cycle regulation. It is often mutated or inactivated in cancer cells and immortal cell lines. We are studying the regulation of p16Ink4a gene expression during cellular senescence.