Aimee Lara Edinger
Developmental & Cell Biology
School of Biological Sciences
Phone: (949) 824-1921
Email: aedinger@uci.edu
http://edingerlab.bio.uci.edu/
http://www.faculty.uci.edu/profile.cfm?faculty_id=5267
Aimee Edinger
Dr. Edinger’s laboratory is studying the relationship between cellular bioenergetics and transformation from the view that constitutive nutrient transporter expression is a primary cause of oncogenic transformation. Work by Dr. Edinger and that of others shows that blocking nutrient transporter destruction is sufficient to prevent apoptosis and transform cells in vitro, suggesting that nutrient uptake stimulates rather than parallels mammalian cell growth. Despite the potential relevance for cancer detection, staging, and treatment, virtually nothing is known about how mammalian nutrient transporter expression is regulated.
Three related projects are currently underway:
- Investigating the links between ceramide, autophagy, and cell death . Diverse stimuli induce apoptosis by stimulating ceramide production. Cancer cells often acquire mutations that decrease ceramide levels, and this can contribute to multidrug resistance. Precisely how ceramide limits cell growth and survival, however, remains unclear. Dr. Edinger had found that ceramide kills cells by rapidly down-regulating nutrient transporter proteins. This work has led to a model where ceramide specifically down-regulates nutrient transporter proteins and the reduction in intracellular nutrient levels stimulates autophagy. If nutrient transporter loss is mild (as with low doses of ceramide) autophagy provides sufficient energy for the cell to survive. If nutrient transporter down-regulation is severe (as with higher levels of ceramide), autophagy is insufficient to meet the metabolic needs of the cell and death from starvation ensues. Many chemotherapeutics kill cells by increasing ceramide levels, and they have found that nutrient transporter down-regulation contributes to their toxicity. These results suggest new chemotherapeutic approaches to treating cancer.
They also have found that the immunosuppressant FTY720 decreases nutrient transporter expression and induces apoptosis by stimulating ceramide production. This drug has been previously shown to suppress tumor growth and metastasis, and they are exploring whether this drug might be an effective cancer therapy.
- Characterizing a conditional Rab7 knockout mouse . Rab7 is a ubiquitously expressed GTPase that facilitates homotypic and heterotypic fusion events between endosomes and lysosomes. They have shown that reducing Rab7 activity results in growth factor-independent cell survival and transformation in vitro by forcing the recycling of endocytosed nutrient transporter proteins. These results have led to the novel hypothesis that Rab7 is a new kind of tumor suppressor that works by facilitating nutrient transporter turnover. They are testing this hypothesis using a conditional knockout mouse developed by Dr. Edinger that lacks Rab7 expression in the T cell compartment. Preliminary experiments have shown that animals with Rab7 deficient T cells have twice as many thymocytes as littermate controls. Thus Rab7 plays an important role in negatively regulating growth or division during T cell development. Experiments will evaluate whether Rab7 T cell knockout mice develop lymphomas at an increased rate in the presence or absence of normal levels of p53.
- Evaluation of Rab7 activation as a chemotherapeutic strategy . The lab has found that multiple oncogenic mutations decrease Rab7 activity. They are now testing the hypothesis that activating Rab7 will slow proliferation and sensitize cancer cells to apoptosis by increasing nutrient transporter down-regulation. Preliminary studies indicate that the activated Rab7 mutant, Q67L, inhibits cellular proliferation and accelerates growth factor withdrawal-induced apoptosis. In addition, Rab7 Q67L expression reverses the growth factor-independent cell survival that results from inhibiting the tumor suppressor, PKC d . They are currently identifying the mechanism by which Rab7 Q67L negatively impacts cell growth and survival.
Selected Publications:
Edinger, A. L., and Thompson, C. B. (2002). Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 13(7), 2276-88.
Edinger, A. L., Cinalli, R. M., and Thompson, C. B. (2003). Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter expression. Dev Cell 5(4), 571-82.
Edinger, A. L., Linardic, C. M., Chiang, G. G., Thompson, C. B., and Abraham, R. T. (2003). Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res 63(23), 8451-60.
Edinger, A. L., and Thompson, C. B. (2003). Defective autophagy leads to cancer. Cancer Cell 4(6), 422-4.
Edinger, A. L., and Thompson, C. B. (2004). An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival. Oncogene 23(33), 5654-63. |
