2128 Natural Sciences I
University of California Irvine
Irvine, CA 92697
Website: Lab Homepage
Apoptosis, cancer, intracellular trafficking
The Edinger Lab studies how cell growth and survival is regulated by growth factors at the level of nutrient transporter expression. This research has important implications for cancer biology and treatment.
My lab is investigating the hypothesis that mammalian cell growth is regulated at the level of nutrient transporter expression. Although the bloodstream constantly supplies mammalian cells with nutrients, signal transduction cascades regulate access to these nutrients by modulating the expression of nutrient transport systems in the cell membrane. By identifying the proteins regulating nutrient transporter expression and trafficking, we expect to gain insight into normal cell biology and identify novel therapeutic targets in cancer. Normal cells become quiescent when restricted for nutrients. Cancer cells, on the other hand, have activated oncogenes that promote growth regardless of the extracellular conditions and deleted the tumor suppressor proteins that allow them to switch to catabolism. Thus, drugs that limit nutrient transporter expression are likely to be selectively toxic to tumor cells.
In order to pursue this idea, my lab has amassed expertise and reagents that allow us to examine how alterations in bioenergetics characteristic of cancer cells interact with conditions that alter nutrient transporter expression. One area of particular interest is autophagy—the adaptive cellular response to the starvation induced by nutrient transporter loss. Through autophagy, (literally, eating one’s self) cells recycle their constituents to provide essential nutrients. We have shown that cells undergoing autophagy in the presence of abundant extracellular nutrients are often cells that have reduced nutrient transporter expression. We have also found that blocking apoptosis (programmed cell death) does not stop nutrient transporter loss from killing cells. The ability of nutrient transporter down-regulation to kill cells necrotically could be useful in cancer therapy as most tumor cells have disabled apoptotic pathways. These studies are also highly relevant to the fields of diabetes and aging.
How is nutrient transporter turnover regulated?
Most scientists are surprised that very little is known about the signals that regulate nutrient transporter expression and trafficking. Although the trafficking of the transferrin receptor (TfR), the LDL receptor (LDLR), and GLUT4 (the insulin sensitive glucose transporter found in adipose and muscle tissue) has been exhaustively studied, amino acid transporters and the broadly expressed GLUT1 are not nearly as well studied. Because the TfR and LDLR deliver their cargo by endocytosis, their regulation is likely to be very different from channel-type transporters like amino acid transporters and GLUT1. Studies of GLUT4 may provide more clues, but this protein trafficks in and out of a special compartment in the cytoplasm and is likely to utilize pathways distinct from those travelled by the vast majority of transporters. My lab has identified signal transduction cascades including the serine-threonine kinase Akt and mammalian TOR (mTOR) as key players in this process. In addition to these kinases, we have identified a downstream regulator of nutrient transporter expression, the small GTPase Rab7. Rab7 promotes membrane fusion events between late endsomes and lysosomes, including those required for nutrient transporter degradation. When Rab7 function is disrupted, it has a dramatic effect on the ability of growth factors to regulate cell growth and survival. Recently, we have made the exciting discovery that ceramide kills mammalian cells by causing a rapid and profound down-regulation of nutrient transporter proteins. Ceramide activates a variety of signaling molecules, and we are investigating which ones might be responsible for the effect of ceramide on nutrient transporter proteins. As ceramide has been linked to cell cycle arrest, death, differentiation, and senescence, our findings may have broad implications for cell biology.
- Peralta EP, Martin BC, and AL Edinger (2010). TBC1D15 is a selective Rab7 GTPase activating protein but mammalian Vps39 does not modulate Rab7 GTP binding status. J. Biol. Chem. 285:16814-21.http://www.ncbi.nlm.nih.gov/pubmed/20363736 This paper identifies proteins that regulate lysosomal dynamics and shows that they modulate growth factor dependence.
- Romero KR, Peralta EP, Guenther GG, Wong SY, and AL Edinger (2009). Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis. Molec. Biol. of the Cell 20:2831-40.http://www.ncbi.nlm.nih.gov/pubmed/19386765?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1 This paper demonstrates that Rab7 activity is regulated by growth factors and that activating Rab7 can kill cells.
- AL Edinger (2008). Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analyzing nutrient transporter expression. Biochem Soc Trans. 2009 Feb;37(Pt 1):253-8. http://www.ncbi.nlm.nih.gov/pubmed/19143642?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=4This review helps to place our recent studies of the effect of ceramide on nutrient transporter expression in context.
- Guenther GG, Peralta EP, Romero KR, Wong SY, Siskind, LJ and AL Edinger (2008). Ceramide starves cells to death by down-regulating nutrient transporter proteins. Proc. Natl. Acad. Sci. 105, 17402–17407. http://www.ncbi.nlm.nih.gov/pubmed/18981422?ordinalpos=1itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumThis paper establishes for the first time that ceramide kills cells through a bioenergetic mechanism.
- Edinger, AL (2007). Controlling cell growth and survival through regulated nutrient transporter expression. Biochem. J. 406:1-12.http://www.ncbi.nlm.nih.gov/pubmed/17645414?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSumComprehensive review of regulated nutrient transporter expression and its role in cellular growth control.