P53 protein structure and function

Tumor Suppression Protein 53 and Effects on Cellular Function and Aging

Tumor Suppression Protein 53 (P53) was originally linked to tumor proliferation and thought to be an oncogene. Research led to an understanding that P53 was in actuality a tumor suppression protein and suppression of the P52 gene is the most widely genetic defect found in tumors (Levine 1991). Further study of p53 and the family of tumor suppression genes led to the understanding that these proteins are responsible for slowing the growth of cells. Through the study of tumor growth and the search for a mechanism that led to accelerated cellular growth in tumors it was found that tumor cells selectively suppress genes that transcribe proteins that lead to apoptosis. The fine line between cells that can divide and live forever and cells that die in a normal life cycle can be heavily impacted by tumor suppression proteins including P53 (Pierra-Smith 1983). Apoptosis, or programmed cell death, is a major factor in aging and the activation of p53 is directly linked both to stabilization and to protection from unchecked growth.

Introduction-Cellular Function and p53

Cell death is a normal process in the life cycle of cells. Cells can either be killed by an exterior factor, termed necrosis or an active process of self-destruction termed apoptosis. Apoptosis is a normal process and requires energy in the cell life cycle and a specific pathway and proceeds with specific signaling pathways that halt functions of cells including transcription and DNA repair (Alberts 2008). The route for apoptosis has many paths depending on the cell life cycle and potential trigger for the mechanism, however, p53 has an important role in one pathway for apoptosis. DNA damage in a cell resulting from poor transcription causes an upregulation of p53 and then a subsequent halt of cellular function at interphase so that the cell has time to repair damage (Marchenko 2000). If the damage is not repaired apoptosis is triggered by p53 and the cell is removed from the local issue without damage to surrounding cells. Figure 1. Below reproduced from (Rodier, 2007) shows the potential pathways for cells in which p53 activity either occurs with a signal or does not occur:

Figure 1: Graphical representation of the impact of p53 on cellular processes.

P53 is always associated with DNA damage. With a defective p53 gene, cells will have a lack of regulation and accumulation of mutations in genes that promotes eventual cancer when a triggered mutation forms cells with rapid growth and lack of apoptosis. For active p53, cells can either be slowed if DNA damage occurs and the damage can be repaired or with improper repair, mutations can occur and with accumulation, cancer can be the outcome. Cells can also be slowed to allow for repair or triggered to promote apoptosis both of which can result in decreased population of cells in organs which can have the effect of aging the organ or surrounding tissue as new cells are not formed to replenish defective or missing ones (Rodier 2007).

The paradox of p53 lies in the relationship between reducing cancer from spontaneous mutations allowing increased survival through simply not developing cancer, and the corresponding decrease in life through normal aging processes where cells in organs are not regenerated at rates that maintain the organs and tissues as static with unlimited renewal. A systematic review of literature for human patients who carry a defective p53 genetic mutation that inhibits p53 suppression show a 2.54:1 higher risk of cancer mortality, however, that same study showed that for patients who reached 85 years or older in the same population of mutated p53, the population with the mutation had a 41% longer life span (Bonafe 2004). Although the biomedical rationale for the precise activity of p53 in human life has not been elucidated for both the optimum prevention of cancer and the highest rate of cellular regeneration in tissue and organs, it is conceivable that there could be a specific balance for the interaction of this protein and increased lifespan.