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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043576-02
Application #
2887817
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Ridge, John P
Project Start
1998-06-01
Project End
2003-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Rutishauser, Rachel L; Martins, Gislâine A; Kalachikov, Sergey et al. (2009) Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31:296-308
Martins, Gislaine A; Cimmino, Luisa; Liao, Jerry et al. (2008) Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival. J Exp Med 205:1959-65
Martins, Gislaine; Calame, Kathryn (2008) Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol 26:133-69
Han, Jin-Hwan; Akira, Shizuo; Calame, Kathryn et al. (2007) Class switch recombination and somatic hypermutation in early mouse B cells are mediated by B cell and Toll-like receptors. Immunity 27:64-75
Magnusdottir, Erna; Kalachikov, Sergey; Mizukoshi, Koji et al. (2007) Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1. Proc Natl Acad Sci U S A 104:14988-93
Kuo, Tracy C; Shaffer, Arthur L; Haddad Jr, Joseph et al. (2007) Repression of BCL-6 is required for the formation of human memory B cells in vitro. J Exp Med 204:819-30
Savitsky, David; Calame, Kathryn (2006) B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion. J Exp Med 203:2305-14
Martins, Gislaine A; Cimmino, Luisa; Shapiro-Shelef, Miriam et al. (2006) Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat Immunol 7:457-65
Shapiro-Shelef, Miriam; Lin, Kuo-I; Savitsky, David et al. (2005) Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J Exp Med 202:1471-6
Tunyaplin, Chainarong; Shaffer, A L; Angelin-Duclos, Cristina D et al. (2004) Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol 173:1158-65

Showing the most recent 10 out of 27 publications