Alexander Varshavsky

avarsh@caltech.edu
Ph.D., 1973, Institute of Molecular Biology, Moscow

Address:  Division of Biology, 147-75,
               California Institute of Technology,
               Pasadena, CA, 91125.

Phone:  626-395-3785.  Fax: 626-440-9821.

Click here for PDF file of Dr. Varshavsky's CV

Dr. Varshavsky's 2005 Interview with Prof. I. Hargittai
("Candid Science"), Imperial College Press, 2006)

Main Research Interests:  The ubiquitin system;  the N-end rule pathway;  new approaches to cancer therapy.

Lab’s History and Current Studies

We are interested in just about everything.  But the brevity of life being what it is compels selectivity. Hence our main subject – the ubiquitin system – chosen partly by preference and partly by accident.

The field of ubiquitin and regulated protein degradation was created in the 1980s, largely through the complementary discoveries by the laboratory of A. Hershko (Technion, Haifa, Israel) and by my laboratory, then at MIT.  These discoveries revealed three sets of previously unknown facts:

1. That ATP-dependent protein degradation involves a new protein modification, ubiquitin conjugation, which is mediated by specific enzymes, termed E1, E2 and E3.
2. That the selectivity of ubiquitin conjugation is determined by specific degradation signals (degrons) in short-lived proteins, including the degrons that give rise to the N end rule.
3. That ubiquitin-dependent processes play a strikingly broad, previously unsuspected part in cellular physiology, primarily by controlling the in vivo levels of specific proteins. My laboratory has shown that ubiquitin conjugation is required for the protein degradation in vivo, for cell viability, and also, specifically, for the cell cycle, DNA repair, protein synthesis, transcriptional regulation, and stress responses. We also cloned and analyzed the first ubiquitin genes, the first specific E3 ubiquitin ligase (UBR1), the first deubiquitylating enzymes (UBP1 and UBP2), and identified the first physiological substrate of the ubiquitin system, the MATalpha2 transcriptional repressor. We showed that ubiquitin-dependent proteolysis involves a polyubiquitin chain of unique topology that is required for protein degradation. We also discovered that the ubiquitin system is capable of subunit selectivity, i.e., it can destroy a specific subunit of a multisubunit protein, leaving the rest of the protein intact and thereby making possible protein remodeling. This fundamental process underlies the cell cycle (replacement of cyclin subunits in cell-cycle kinases), the activation of transcription factors such as, for example, NF-kappaB, and many other processes. Together, these biological (function-based) studies in the 1980s resulted in the overall discovery of physiological regulation by intracellular protein degradation.

The Hershko laboratory produced the first of three fundamental advances, in 1978-1983 (item 1), and my laboratory produced the other two, in 1984-1990 (items 2 and 3).

The above complementary insights led to enormous expansion of the ubiquitin field in the 1990s and afterward. This field is now one of the largest arenas in biomedical science, the point of convergence of many disparate disciplines.

My lab’s biological discoveries in the 1980s yielded the modern paradigm of the central importance of regulated proteolysis for the control of the levels of specific proteins in vivo, as distinguished from their control by transcription and protein synthesis. In other words, these advances revealed that the control through regulated protein degradation rivals, and often surpasses in significance the classical regulation through transcription and translation.

This radically changed understanding of the design of biological circuits has major ramifications for medicine, given the astounding functional range of the ubiquitin system and the multitude of ways in which ubiquitin-dependent processes can malfunction in disease or in the course of aging, from cancer and neurodegenerative syndromes to perturbations of immunity and many other illnesses, including birth defects.

For accounts of the early history of the ubiquitin field, see:

Hershko, Ciechanover and Varshavsky (2000) The ubiquitin system. Nature Medicine 6, 1073-1081;

Varshavsky (2006) The early history of the ubiquitin field. Protein Science 15, 647-654.

My laboratory continues to study ubiquitin-dependent processes, with a focus on the N-end rule pathway of protein degradation, which we analyze in the mouse, in the yeast Saccharomyces cerevisiae, and in prokaryotes. The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Although prokaryotes lack the ubiquitin system, the N-end rule pathway (its ubiquitin-independent versions) is present in them as well.

We are also interested in developing new approaches to therapy of currently intractable diseases, particularly cancer. For recent ideas in this area that we are working on in the lab, see Varshavsky (2007) Targeting the absence: homozygous DNA deletions as immutable signposts for cancer therapy. Proc. Natl. Acad. Sci. USA 104, 14935-14940.

Selected publications by the Varshavsky laboratory

Honors & Awards

Fellow, American Academy of Arts and Sciences, 1987.
Member, National Academy of Sciences, 1995.
Fellow, American Academy of Microbiology, 2000.
Member, American Philosophical Society, 2001.
Foreign Associate, European Molecular Biology Organization, 2001.
Foreign Member, Academia Europaea, 2005.

Merit Award, National Institutes of Health, 1998.
Novartis-Drew Award in Biomedical Science, 1998.
Gairdner International Award, Gairdner Foundation, Canada, 1999.
Sloan Prize, General Motors Cancer Research Foundation, 2000.
Lasker Award in Basic Medical Research, Lasker Foundation, 2000.
Shubitz Prize in Cancer Research, University of Chicago, 2000.
Hoppe-Seyler Award, Society for Biochem. & Mol. Biology, Germany, 2000.
Pasarow Award in Cancer Research, Pasarow Foundation, 2001.
Merck Award, American Society for Biochemistry and Molecular Biology, 2001.
Wolf Prize in Medicine, Wolf Foundation, Israel, 2001.
Max Planck Research Award, Germany, 2001.
Massry Prize, Massry Foundation, 2001.
Horwitz Prize, Columbia University, 2001.
Wilson Medal, American Society for Cell Biology, 2002.
Stein and Moore Award, Protein Society, 2005.
March of Dimes Prize in Developmental Biology, March of Dimes Foundation, 2006.
Griffuel Prize in Cancer Research, Assoc. pour la Rech. Cancer, France, 2006.
Gagna and Van Heck Prize, Fonds National de la Rech. Scientifique, Belgium, 2006.
Schleiden Medal, Deutsche Akademie der Naturf. Leopoldina, Germany, 2007.