B LYMPHOCYTE INDUCED MATURATION PROTEIN

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Blimp-1(B lymphocyte induced maturation factor) was first identified as a master regulator of B-cell development. This zinc finger protein is induced upon B cell differentiation and is sufficient to drive the lymphoma line BCL1 to adopt a terminally differentiated phenotype. The PI's group has recently shown that Blimp-1 represses c-myc gene transcription in B cells. Since c-Myc is required for cell cycle progression and is also known to block terminal differentiation, it makes sense that the c-Myc gene would be repressed by a protein which triggers terminal differentiation. Furthermore, the PI presents preliminary data showing that induction of Blimp-1 is not restricted to B cells but also occurs upon terminal differentiation of two promyelocytic cell lines. In addition, several normal tissues, including heart and brain, have steady-state levels of Blimp-1 mRNA similar to that found in spleen. Taken together these data suggest that Blimp-1 may play a role in terminal differentiation of many cell lineages. As a repressor of the c-myc gene, Blimp-1 could function as a tumor suppressor since elevated levels of c-Myc are known to play a casual role in oncogenesis of many tumors. The blimp-1 gene is located on human chromosome 6q21-22. Interestingly, subsets of lymphocytic, breast, melanoma and other tumors have non-random deletions in this regions of chromosome 6, suggesting the presence of a tumor suppressor. The investigator proposes an analysis of the biological roles played by Blimp-1 in terminal differentiation and, possibly, as a tumor suppressor. The experiments on the role of Blimp-1 in terminal differentiation will take advantage of transgenic mice and several cultured cell models for terminal differentiation. She will also use sensitive in situ hybridization methods to determine the normal expression pattern of Blimp-1 mRNA during embryonic development and in adult tissues. The possible tumor suppressor activity of Blimp-1 will be tested by inducing ectopic expression of the protein in a variety of tumor lines. She also proposes systematic analyses of biochemical mechanisms to determine how Blimp-1 represses transcription and how it is induced during terminal differentiation. The PI's laboratory has extensive experience studying transcriptional regulation and B-cell development. This project draws together many facets of the investigator's previous work and focuses on an intriguing and potentially critical protein which has not received much attention until now.