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Biochemistry



The members of the Department of Biochemistry study the biochemical events that regulate cell growth and differentiation and that are associated with transformation when genes are altered. One common theme with the department is the signal transduction pathways and mechanisms that regulate the life or death of cells through control of apoptosis, particularly hematopoietic cells. Several groups work on members of the Bcl-2 family of proteins that function to either protect cells from apoptosis or are responsible for inducing apoptosis. For example, studies have demonstrated an essential role for the mitochondrial protein, Mcl-1, in survival from apoptosis of a variety of cells including all lineages of hematopoietic cells. Current studies are focused on how the protein is regulated, particularly by cytokines, and how it functions to protect cells from the onset of apoptosis. Another group has focused on the mitochondrial protein Hax1, which is a distant member of the Bcl-2 family of proteins. Loss of Hax1 results in increased apoptosis and concomitant loss of both hematopoietic cells and neurons. In children, others have shown that loss of Hax1 is responsible for one form of congenital neutropenia due to increased apoptosis of granulocytes. Recent studies, collaborative between departmental groups, have shown that the critical function of Hax1 in the mitochondria is to form a complex with a mitochondrial protease termed Parl on the inner mitochondrial membrane. In the complex, Hax1 is responsible for binding to another mitochondrial protease termed HtrA2 in a manner in which Parl can cleave a region of HtrA2 to allow it to become an active protease in the inter mitochondrial membrane space. The studies further identified a potential substrate for HtrA2; namely, the Bcl-2 family member Bax which is responsible for causing mitochondrial damage and subsequent activation of the apoptotic pathways. Studies among the groups are further focusing on establishing the mechanisms by which cells regulate both for and against apoptosis.

One group has a long standing interest in the functions of the tumor suppressor gene, p53. Collaborations with clinical investigators identified a novel mutation in p53 assocaited with adrenocortical carcinomas in children. Studies with structural biologists found that the mutation uniquely affects the structure of the protein and this accounts for the remarkable specificity of tumor types associated with this mutation. The group also seek s to identify genes that are regulated by p53 and have focused on two genes, Puma and ei24. Puma is a pro-apoptotic member of the Bcl-2 family and the group has shown that removing the genes allows cells to survive a number of insults that would normally induce apoptosis. Studies are exploring the mechanisms by which Puma can activate the apoptotic pathways. Similarly genetic approaches are pursuing the functions of Ei24.

Another group has a long standing interest in the sequence of events that are involved in the production of erythroblasts. The aspects that have been studies include the identification of genes that contribute to the susceptibility to erythroleukemias and the regulation of the transcription of the globin gene by factors such as Nfe2. Screening of genes expressed during differentiation identified a novel Bcl-2 family member-like gene termed NIX. Recent studies have found that this protein is required for the efficient elimination of mitochondrial during differentiation. Studies are focusing on the mechanisms by which Nix signals the phagosome pathway to mediate this function.

Regulation of transcription is a critical component of virtually all aspects of hematopoiesis and one group focuses on two of the most important co-activators, namely Cbp and p300. Studies over several years have used largely genetic approaches to functionally define individual domains of these large transcriptional regulators. As definitive information because available, more mechanistic insights are being pursued by a variety of biochemical approaches. Lastly, an important component of transcriptional regulation involves the chromatin structure in which a particular gene is located. Another group in the department has focused their research over several years into the factors and sequence of events that are involved in the formation of centromeric heterochromatin, particularly in yeast as a model organism. One critical protein is termed Chp1 and the group is identifying the domains involved and the basis for recruitment to areas where heterochromatin formation will occur. Current models involve the recruitment of Chp1 by recognition of specific histone modifications which, in turn, provides a recognition site for the recruitment of another complex, termed RITS, which contribute to heterochromatin formation. Insights into these mechanisms are critical to understanding the events that are critical for cell division.

James Ihle, PhD, chairs the Biochemistry Department at St. Jude.


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