Wednesday, September 2, 2015

Tumor Suppressor p53 and the Clearance of Apoptotic Cells

Within the human body, with its complex array of highly differentiated organs and tissues, it is estimated that more than a billion cells die each day.  Most of these deaths arise from a natural process referred to as apoptosis – programmed cell death.  Since apoptosis is integral to the functioning of a healthy organism, its mechanism has been the focus of study for many years. 

In addition to the process of apoptosis, there also exists a mechanism for the efficient processing and clearance of the cellular debris that is a direct result of apoptosis.  Otherwise, the accumulation of released substances from dead cells could function as autoantigens and elicit an undesirable immune response against normal tissue resulting in autoimmune diseases.  In addition, chronic inflammation and developmental abnormalities could result from the buildup up cellular debris.  It has been established that the immune response to apoptotic cells involves the mobilization of phagocytic cells whose function is to engulf the dead or dying cells.  This process necessarily requires the expression of immune tolerance in order to prevent an autoimmune response.

The tumor suppressor  p53 protein has long been associated with the mechanism of apoptosis.  However, little has been established in regards to the putative role of p53 in the clearance of cellular debris that results from apoptosis.

Dr. Kyoung Wan Yoon and his colleagues from the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA have focused their research efforts on the elucidation of the role of p53 in the clearance of post apoptotic cells and the establishment of tolerance to self-antigens.

What they have shown is the following.  As a result of stress upon a cell that leads to p53-mediated apoptosis, p53 triggers the production of a protein product from the so-called “Death Domain1a (DD1a)” gene.  DD1a functions as a ligand that is instrumental in the binding of the apoptotic cell to the phagocytic immune cell that will eventually engulf the dead cell.  Once this engulfment occurs it subsequently triggers the binding of an inhibitory T cell that ensures tolerance to self-antigens; thereby, preventing untoward reactions that could lead to a disease state.

This kind of work is extremely valuable in furthering the understanding of the mechanism of self-tolerance.  Such knowledge may prove instrumental in determining the underlying mechanisms involved in auto-immune disease.

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