Tumor suppression

The tumor suppressor gene TP53 and its gene product—a veritable swiss Army knife of cellular regulation—have been the targets of intense study since their discovery in 1979. 1-3 indeed, a PubMed search for the term " p53 " retrieves more than 68 000 citations, and more than 100 physical or genetic interactions with TP53 have been identified to date. its importance in cancer biology was recognized immediately upon its discovery, and Science honored p53 as the " Molecule of the year " some 20 y ago. Despite the intensity of this research, spanning more than 3 decades, the mechanisms by which p53 coordinates diverse cellular functions remain enigmatic. A study by DeMicco and colleagues sheds new light on the tumor suppressor roles of p53, showing that it performs different functions depending on its cellular and developmental context. 4 The canonical role of TP53 is as a tumor suppressor gene that responds to DNA damage. However, diverse roles for TP53 in coordinating cellular response to a range of stresses have been discovered. it is now known that TP53 responds to oxidative stress and oxidized DNA; monitors and regulates aspects of cellular metabolism; governs proper chromosome segregation; controls cell cycle arrest in response to cellular stressors; induces apopto-sis; and regulates autophagy and senescence. 5 Reflecting its key role in coordinating stress responses, TP53 is the single most frequently mutated gene in human cancer, with partial or complete loss of function occurring in 60% of tumors. 6,7 This observation, together with a multitude of studies in model systems, has demonstrated a role for TP53 in tumor suppression in a host of different cell and tissue types. DeMicco et al. have used an elegant mouse modeling approach to begin unraveling the key tumor suppressor functions of TP53 in T-cell lymphomas. 4 The authors use the power of conditional TP53 deletion to inactivate it at varying stages of T-cell development and to characterize the subsequent tumors. Using Figure 1. Context dependent integration of p53 tumor suppressor activities. The study by DeMicco and colleagues shows that the role that p53 plays in suppressing neoplastic transformation can vary by developmental stage within a single cell lineage. 4 Their data show that inactivation of TP53 in HsC results in tumors with translocations that do not involve antigen receptors, while inactivation in DN thymocytes predisposes to lymphoma with antigen receptor translocations. These lymphomas contrast with the aneuploid tumors that …