Beth Levine, M.D.
Professor of Internal Medicine and Microbiology
Chief, Division of Infectious

Office:  214-648-3480
Email:  beth.levine@utsouthwestern.edu

Our laboratory uses molecular and genetic approaches in mice and model organisms to study the role of specific host genes and cell biology pathways involved in infectious diseases, cancer biology, and development.  The primary focus of our studies is on the cellular pathway of autophagy.

Autophagy is the major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles.  It involves the rearrangement of subcellular membranes to sequester cargo for delivery to the lysosome where the sequestered material is degraded and recycled.  For many decades, it has been known that autophagy occurs in a wide range of eukaryotic organisms and in multiple different cell types during starvation, cellular and tissue remodeling, and cell death.  However, until recently, the biological functions of autophagy have been largely unknown.  The identification of a set of evolutionarily conserved genes that are essential for autophagy has opened up new frontiers for understanding the role of autophagy in diverse biological processes. 

Our laboratory identified the first known mammalian autophagy gene, beclin 1, a haploinsufficient tumor suppressor gene that encodes a Bcl-2-interacting protein.  Using reverse genetic approaches, we have demonstrated a role for beclin 1 and the autophagy pathway in dauer development and lifespan extension in C. elegans, in mouse embryonic development and tumor suppression, and in innate immunity against viral infections in both plants and mammals.  We have also found that the eIF2α kinase signaling pathway (including the interferon-inducible antiviral molecule, PKR) positively regulates autophagy and that the oncogenic insulin-like signaling pathway negatively regulates autophagy.  We are continuing to use both mouse and C. elegans genetic model systems to explore the role of autophagy in normal development and lifespan control; the mechanisms by which autophagy genes function in tumor suppression; the mechanisms by which beclin 1 functions in autophagy; the interrelationship between autophagy and apoptosis pathways; and the role of autophagy as a host defense mechanism against certain viruses and intracellular bacteria (e.g. Sindbis virus, herpes simplex virus, Salmonella typhimurium, Mycobacteria avium).  Insights gained from these studies are expected  to lead to new genetic and pharmacologic approaches that may be useful in the prophylaxis or treatment of certain human diseases (e.g. infectious diseases, cancer) and in the prevention of aging.

Selected Publications:

Liang XH, Kleeman LK, Jiang HH, Gordon GW, Goldman JE, Berry G, Herman B, Levine B. Protection against fatal Sindbis virus encephalities by Beclin a novel Bcl-2-interacting protein.  J. Virol. 1998; 72: 8586-8596.

Liang XH, Jackson S, Brown K, Rothstein R, Hishoosh H, Levine B.  Introduction of autophagy and inhibition of tumorigenesis by beclin 1.  Nature.  1999; 402:672-676.

Talloczy Z, Jiang W, Virgin HW, Leib DA, Scheuner D, Kaufman RJ, Eskelinen E-L, and Levine B.  Regulation of starvation-and virus-induced autophagy by the eIF2α kinase pathway.  Proc. Natl.Acad. Sci USA 2002;99:190-195.

Melendez A, Talloczy Z, Seaman M, Eskelinen E-L, and Levine B.  Autophagy genes are essential for dauer development and lifespan extension in C. elegans.  Science 2003; 301:1387-1391.

Qu X, Yu J, Baghat G, Hibshoosh H, Troxel A, Mizushima N, Ohsumi Y, Cattoretti G, and Levine B.  Promotion of tumorigenesis by heterozygous deletion of the beclin 1 autophagy gene.  J. Clin. Invest. 2003; 112:1809-1820.

Levine B, Klionsky D.  Development by self-digestion:  molecular mechanisms and biological functions of autophagy.  Development Cell 2004;6:463-467.