Syk survival signals in Epstein-Barr virus (EBV)+ B cell lymphomas
Abstract/Contents
- Abstract
- Spleen tyrosine kinase (Syk) mediates a diverse array of contextually dependent cellular outcomes, from its well-characterized role in adaptive immune receptor signaling to the novel and unexpected roles in innate immune recognition, cellular adhesion, vascular development, and osteoclast maturation. Many of these novel functions involve non-canonical activation of Syk. The ultimate functional outcome of Syk signaling depends on the cellular context, the mechanism of activation, and the downstream signaling mediators utilized. Herein, we address both the mechanism of Syk activation and the downstream mediators of Syk that drive survival in Epstein-Barr virus (EBV)+ B cell lymphomas. Using B cell lines stably-transfected with a signaling inducible chimeric of the primary EBV oncogene latent membrane protein 1 (LMP1), we uncover the first evidence of non-canonical Syk activation by a viral protein. We also demonstrate that activation of both Syk and the Src family kinase Fyn are involved in the initiation of PI3K/Akt signaling by LMP1. We utilize small molecule inhibition and siRNA knockdown of Syk to establish that the regulation of apoptosis is a critical outcome of Syk signaling in EBV+ B cell lymphomas. Navigating downstream, we demonstrate that Syk promotes survival of EBV+ B cell lymphomas through a PI3K/Akt-dependent stabilization of the caspase inhibitor XIAP. Finally, we evaluate the therapeutic potential of inhibiting the Syk survival signal in EBV+ B cell lymphomas. PI3K/Akt inhibition, but not Syk inhibition, significantly reduces tumor burden in a xenogeneic model of EBV+ B cell lymphomas. Surprisingly, Syk inhibition results in tumor migration and expansion in adjacent inguinal lymph nodes. Our mechanistic characterization of Syk signaling in EBV+ B cell lymphomas reveals a novel role for Syk in both survival and migration of EBV+ B cell lymphomas. Taken together, our data also suggests that EBV drives creates a requirement for PI3K/Akt signaling for the survival of EBV+ B cell lymphomas, reminiscent of oncogene addiction, through Syk activation by LMP1 and LMP2a.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Hatton, Olivia Louise |
|---|---|
| Associated with | Stanford University, Program in Immunology. |
| Primary advisor | Martinez, Olivia |
| Thesis advisor | Martinez, Olivia |
| Thesis advisor | Jones, Patricia |
| Thesis advisor | Lewis, David |
| Thesis advisor | Utz, Paul |
| Advisor | Jones, Patricia |
| Advisor | Lewis, David |
| Advisor | Utz, Paul |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Olivia Louise Hatton. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2011. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Olivia Louise Hatton
Also listed in
Loading usage metrics...