THE EDINGER LAB
PI: Aimee L. Edinger, VMD/PhD
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.
What are growth factors and why should we study them?
Unicellular organisms such as yeast grow and divide in response the level of extracellular nutrients available: a yeast cell placed in the midst of abundant nutrients will rapidly proliferate (see right). When these nutrients are exhausted, the yeast cells will sporulate or die. Following the evolutionary transition from unicellular to multicellular organisms, this nutrient-limited style of cell growth could no longer be sustained. The cells of multicellular organisms are constantly bathed in nutrients (supplied via the bloodstream) and yet cell growth and division must be tightly regulated to maintain tissue and organismal homeostasis. Growth factors evolved as a mechanism to enforce cooperative, controlled cellular growth in multicellular organisms. Growth factors are extrinsic factors produced by other cells that regulate growth, proliferation and survival in all mammalian cell types. When cells grow beyond homeostatic limits, growth factors become limiting and cells atrophy, cell cycle arrest, and undergo apoptosis. When cells accumulate mutations that release them from growth factor regulation, the result is cellular transformation. All tumor cells are capable of growth factor-independent growth and survival. By studying the mechanisms by which growth factors control cell growth and survival, we hope to better understand the biochemical pathways involved in the development of cancer and to develop novel strategies for interfering with these pathways in tumor cells and thereby develop new cancer chemotherapeutics.
What does this have to do with nutrient transporter proteins?
Returning to the unicellular model of cell growth, yeast cells express nutrient transporter proteins on their surface in a pattern that is regulated by the nutrients available in the extracellular space. Nutrient sensing pathways are coupled to signal transduction pathways that control the transcription and translation of nutrient transporter proteins. In addition, these signal transduction pathways cause the cell surface expression and turnover of nutrient transporters to change in response to extracellular conditions. Studies performed in the Edinger lab have contributed to the idea that growth factors have actually co-opted many of the pathways linked to nutrient regulated growth in unicellular organisms and used them to control mammalian cell growth. Growth factors activate signal transduction pathways that result in the expression of transporters for a wide variety of nutrients on the cell surface. Without growth factors, the lack of nutrient transporters means that a cell can't eat. Of course, mammalian cells cannot grow without extracellular nutrients, but we can think of growth factors as providing a “permission signal” for cells to access extracellular nutrients , thereby controlling cell growth and survival. When growth factors are limiting, cells actually starve to death in rich medium due to the inability to access extracellular nutrients following the loss of nutrient transporter protein expression.
What proteins are involved in nutrient transporter turnover? We have found that oncogenic forms of the Akt serine-threonine kinase support growth factor-independent nutrient transporter expression and that this function is essential for Akt to act as an oncogene. Mammalian TOR (mTOR), the homolog of a yeast kinase that serves as a central regulator of nutrient transporter expression in response to changing extracellular nutrient levels, is similarly involved in this process. In addition to these kinases which regulate many other biochemical pathways independent from their effects on nutrient transporter expression, we have identified a downstream regulator of nutrient transporter expression, the small GTPase Rab7. Rab7 activity is restricted to modulating membrane fusion events between late endsomes and lysosomes. However, when Rab7 function is disrupted, it has a dramatic effect on the ability of growth factors to regulate cell growth and survival. Cells in which Rab7 function is blocked maintain higher levels of nutrient transporter proteins despite growth factor withdrawal (see figure to left) and are capable of significant growth factor-independent cell survival. In addition, cells with decreased Rab7 activity form colonies in soft agar, a classic in vitro test for cellular transformation.In summary, the laboratory is currently focused on understanding the biochemical mechanisms by which signal transduction cascades, such as those including Akt and mTOR, regulate nutrient transporter expression and on identifying which downstream molecules, such as Rab7 and RILP (Rab7 interacting lysosomal protein), actually control nutrient transporter expression and turnover in response to growth factor availability.
What could I work on in the lab?
If you are interested in these ideas and are considering joining in the lab, please email or call Dr. Edinger to make an appointment to discuss possible projects in detail. Current areas of active investigation include: the biochemical mechanisms by which mTOR regulates transporter turnover, Rab7/RILP regulation, involvement of ubiquitination in the control of nutrient transporter expression, evaluation of chemotherapeutic agents whose MOA may include the control of transporter turnover. These problems are approached using molecular and biochemical techniques, mammalian tissue culture, and mouse model systems.
DR. EDINGER'S HISTORY
After growing up in San Diego , I did my undergraduate work at UC Davis where I originally intended to go to vet school. I signed up to work with UC Davis veterinary researchers studying the effects of altitude on exercise physiology in horses and emus and enjoyed research so much that I ended up doing a senior research project in a molecular biology lab. These experiences convinced me that I should enter the combined veterinary/PhD training program at the University of Pennsylvania . After graduating from vet school in 1996, I completed my PhD in the lab of Dr. Bob W. Doms studying the envelope proteins of HIV and SIV (the simian form of the virus). I ended up staying at PENN for my postdoc, but switched fields entirely to work on growth factor regulation of cell growth and survival in the lab of Dr. Craig B. Thompson who had just moved to PENN from the University of Chicago . The current focus of the lab is to continue studies that I initiated in the Thompson lab.
SELECTED PUBLICATIONS ON THESE TOPICS
Edinger AL, Cinalli RM, and CB Thompson (2003). Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter expression. Dev. Cell 5:571-582.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14536059
Preview: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14580329
If you only read one paper about what we do, this should be it! This work is exciting because there are very few examples of molecules not directly involved in signal transduction that have such a profound effect on cell growth and survival. In addition, Rab7 had never been linked to transformation. This work suggests that Rab7 may in fact represent a whole new class of tumor suppressor proteins.
Edinger AL and CB Thompson (2002). Akt maintains cell size and survival by increasing nutrient uptake via an mTOR-dependent mechanism. Molec. Biol. of the Cell 13:2276-2288.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12134068
Akt has long been studied by the diabetes field for its ability to control glucose transporter expression. This paper shows for the first time that growth factors and Akt regulate not just glucose uptake, but global nutrient transporter protein expression and that this activity is important for Akt-mediated growth factor-independent survival. In addition, these effects of Akt are identified as dependent on mTOR activity.
Edinger AL, Linardic CM, Chiang GG, Thompson CB, and RT Abraham (2003). Differential effects of rapamycin on mTOR signaling functions in mammalian cells. Cancer Research 63:8451-8460.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14679009
It has long been known that yeast TOR possesses an essential function that is not inhibited by the drug rapamycin. Recent papers, including this one, have shown that mTOR also has rapamycin-insensitive activities. As rapamycin analogs are currently in stage III clinical trials as cancer chemotherapeutics, it is critically important to understand which mTOR-dependent functions are inhibited by this drug.
Edinger, AL and CB Thompson (2004). Death by design: apoptosis, necrosis, and autophagy. Curr. Opin. Cell Biol. 16:663-669.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15530778
This review highlights recent data surrounding the role of necrosis and autophagy in programmed cell death. Non-apoptotic forms of programmed cell death are currently hot!
Edinger AL and CB Thompson (2002). Antigen presenting cells control T cell proliferation by regulating amino acid availability. Proc. Natl. Acad. Sci., USA 99:1107-1109.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11830651
This commentary highlights the ways in which immune cell function is modulated at the level of nutrient access. It is one of my favorites!