Human cancers have in common several acquired phenotypes that distinguish them from normal cells. For example, normal cells have limited proliferative potential and eventually undergo irreversible growth arrest or senescence. In contrast, cancer cells escape senescence and display indefinite proliferative potential or cellular immortality.
In normal human cells, induction of senescence depends upon the pRB and p53 pathways. Each of these pathways is thought to be inactivated in virtually all human cancers, thus contributing to cell immortality. The pRB and p53 pathways are known to acutely inhibit cell cycle progression through inhibition of the E2F transcription factors and cyclin/cdk2 activity respectively. However, we know surprisingly little of how these pathways initiate the irreversible cell cycle arrest that characterizes senescence.
Recently, Lowe and coworkers showed that senescence was accompanied by profound changes in chromatin structure (M. Narita et al., Cell. 113:703, 2003). Specifically, they showed that senescent cells accumulated senescence associated heterochromatin foci (SAHF). These are defined as senescence-specific domains of transcriptionally silent heterochromatin that contain proliferation-associated genes, such as E2F target genes. Intuitively, it seems likely that incorporation of proliferation-associated genes into heterochromatin could contribute to the irreversible cell cycle arrest characteristic of senescence. A major goal of the lab it to understand the molecular events leading to these changes in chromatin structure in senescent cells.