Department of Biochemistry
School of Medicine & Biomedical Sciences
Faculty

 

   LEE ANN GARRETT SINHA, Ph.D.
   Assistant Professor

   email: leesinha@buffalo.edu

   Link to BMS 511 Lecture [PPT]

The Biological Role of the Ets Family of Transcription Factors in Autoimmunity and Cancer

The objective of my research is to understand the roles of Ets transcription factors in both normal development and cancer.  Several members of the Ets family are highly expressed in immune cells including B cells and T cells.  My lab studies the function of three of these Ets proteins (PU.1, Spi-B and Ets-1) in controlling the differentiation of B and T cells from hematopoietic stem cells as well as in controlling later stages of B cell differentiation into antibody-secreting cells.  We have shown that PU.1 and Spi-B are required fornormal B cell maturation and for B cells to secrete IgG antibodies in response to protein antigens.  In contrast, the absence of Ets-1 leads to excessive antibody production by B cells in the absence of antigenic stimulation.  This excessive differentiation of B cells is correlated with the development of autoimmune disease in Ets-1 knockout mice.  Ets-1 is also necessary for normal development of CD8+ T cells in the thymus.

In addition to our interest in the role of Ets proteins in regulating the normal development of hematopoietic cells, we are also interested in the role of Ets family members in tumor formation and progression.  Human tumors frequently over-express one or more members of the Ets gene family.  Ets-1 is one of the Ets genes that has been shown to be over-expressed in a large number of different types of human cancers.  Human tumors that over-express Ets-1 tend to be more aggressive and metastatic than Ets-1 negative tumors.  To further explore the relationship between Ets-1 expression and tumor formation and metastasis, we have recently developed a transgenic mouse model in which we can inducibly express Ets-1 in a variety of tissues at different stages of development.  Using this model system, we have induced Ets-1 in the epithelial cells of stratified squamous epithelial tissues (skin, oral mucosa, esophageal mucosa, etc.) in adult mice.  Interestingly, induction of Ets-1 in these tissues leads to a dramatic hyper-proliferative phenotype and altered terminal differentiation of the tissues.  These results support a role for Ets-1 in mediating early events in squamous cell carcinogenesis.

Current studies in the lab focus on understanding the molecular mechanisms by which Ets proteins regulate B and T cell development and terminal differentiation as well as tumor formation and progression. These studies will employ a variety of common immunological (flow cytometry, ELISA, ELISPOT, adoptive transfer) and molecular biological (DNA microarray analysis, Western blot, Northern blot, gel shift assays, transfection, and chromatin immunoprecipitation, retroviral transduction) techniques.

Selected Recent Publications

John, S.A., Clements, J.L., and Garrett-Sinha, L.A. (2007) Ets-1 regulates plasmacytic differentiation by interfering with the activity of the transcription factor Blimp-1.  Submitted.

Nagaleekar, V.K., Diehl, S., Juncadella, I., Charland, C., Garrett-Sinha, L.A., Muthusamy, N., Anguita, J. and Rincón, M. (2007) Ets1-dependent IP3R3 expression in naïve CD4+ T cell is required for cytokine gene expression.  Submitted.

Clements, J.L., John, S.A., and Garrett-Sinha, L.A. (2006) Impaired generation of CD8+ thymocytes in Ets-1-deficient mice.  J Immunol. 177:905-912.

Wang, D., John, S.A., Clements, J.L., Percy, D.H., Barton, K.P. and Garrett-Sinha, L.A.  (2005) Ets-1 deficiency leads to altered B cell differentiation, hyper-responsiveness to TLR9 and autoimmune disease. International Immunology, 17:1179-1191.

Garrett-Sinha, L.A., Hou, P., Wang, D., Grabiner, B., Araujo, E., Rao, S., Yun, T.J., Clark, E.A., Simon, M.C. and Clark, M.R.  (2005) Spi-1 and Spi-B control the expression of the Grap2 gene in B cells.  Gene, 353:134-146.

Lefebvre, J.M., Haks, M.C., Carleton, M.O., Rhodes, M., Sinnathamby, G., Simon, M.C., Eisenlohr, L.C., Garrett-Sinha, L.A., Wiest, D.L.  (2005) Enforced expression of Spi-B reverses T lineage commitment and blocks b-selection.  J Immunol. 174:6184-6194.

Hu, C-J, Rao, S., Ramirez-Bergeron, D.L., Garrett-Sinha, L.A., Gerondakis, S., Clark, M.R., and Simon, M.C.  (2001) PU.1/Spi-B regulation of c-rel is essential for mature B cell survival.  Immunity, 15:545-555.

Garrett-Sinha, L.A., Dahl, R., Rao, S., and Simon, M.C.  (2001) PU.1 exhibits partial functional redundancy with Spi-B, but not with Ets-1 or Elf-1.  Blood 97:2908-2912.

Rao, S., Garrett-Sinha, L.A., Yoon, J., and Simon, M.C.  (1999) The Ets factors PU.1 and Spi-B regulate the transcription in vivo of P2Y10, a lymphoid-restricted heptahelical receptor.  J. Biol. Chem. 274:34245-34252.

Garrett-Sinha, L. A., Su, G. H., Rao, S., Kabak, S., Hao, Z., Clark, M. R., and Simon, M. C.  (1999) PU.1 and Spi-B are required for normal B cell receptor-mediated signal transduction.  Immunity 10:399-408.

Su, G. H., Chen, H. M., Muthusamy, N., Garrett-Sinha, L. A., Baunoch, D., Tenen, D. G., and Simon, M. C.  (1997) Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B.  EMBO J. 16:7118-7129.

The Lee Ann Garrett-Sinha Lab: from l to r:
Lee Ann Garrett-Sinha, Shinu John (student); Irene Kulik (technician).

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