The Role of Pro-apoptic BCL-2 Family Bid in the DNA Damage Response
Programmed cell death, also called apoptosis, is a normal process that the body uses to rid itself of damaged cells. Cancer cells acquire the ability to evade this process, allowing them to live too long, as well as to resist therapeutic treatments such as chemotherapy and radiation. Cancer cells have genetic defects in this normal cellular “suicide” program that governs cell death and survival. The discovery of the BCL-2 family of genes uncovered the underlying genetic mechanism of this regulation, as well as an entirely new class of oncogenes: those that govern cell death rather than cell proliferation. The founder of this family, the Bcl-2 gene, was found to be located at the chromosomal breakpoint of t (14; 18)-bearing human B-cell lymphomas. Since then, a whole family of related proteins, called the BCL-2 family after its founding member, has been discovered that regulates cell death. Dr. Zinkel’s work showed that the pro-death BCL-2 family member BID is important in preventing cancer development in the blood cells of mice (leukemia). The best model to test the role of a gene in normal development is an animal model in which the gene of interest has been disrupted. The deletion of BID prolongs the lives of myeloid cells, fostering the accumulation of additional genetic mutation and promoting the development a fatal disorder resembling the human disease chronic myelomonocytic leukemia (CMML). These studies reveal that BID plays a critical role in preserving genomic integrity, maintaining myeloid homeostasis (metabolic equilibrium), and suppressing tumor growth and normal immune (myeloid cell behavior). The occurrence of cancer in the BID-deficient mice underscores the importance of apoptotic control in the development of chronic leukemia and related disorders. Tumor progression is a multi-step process in which a succession of genetic changes leads to uncontrolled cell growth, a hallmark of cancer. Paradoxically, many of the agents currently used to treat cancer can accelerate the acquisition of these genetic changes in the event that the treated cells do not die, potentially leading to further tumor progression and/or resistance to therapy. Dr. Zinkel’s current studies are focused on identifying the proteins that interact with BID following this DNA damage and how BID functions during this process. Dr. Zinkel’s goal is to uncover the genes and the proteins that direct the decision of a cell to repair its DNA or to die, providing important clues in the search for therapeutic targets.