Professor of Biochemistry at the Technion – Israel Institute of Technology
More than twenty-five years ago, Avram Hershko began studying how cells rid themselves of unwanted or damaged proteins. With the help of his colleagues, Hershko discovered the ubiquitin system and eventually determined that it impacts major physiological processes in the body. Scientists now know that it is involved in regulating cell division, aids in controlling embryonic development, and helps maintain the immune system. It is implicated in a number of diseases as well, including cervical cancer caused by the human papilloma virus.
Research Group :
Proteins carry out most chemical and physical processes in cells and regulate basic cellular functions such as cell division and development. Though much research has been done on how proteins are made, relatively little attention has been paid to the problem of how cellular proteins are destroyed with a high degree of specificity and sophistication. Previous work in Pr Hershko's laboratory has shown that specific proteins are tagged for destruction by attachment to a small protein, ubiquitin. His research group has also delineated many of the basic enzymatic reactions in the ubiquitin-mediated protein degradation system.
More recently, he became interested in the roles of ubiquitin-mediated protein degradation in the control of the cell division cycle. Cell division is driven by oscillations in the levels of regulatory proteins such as cyclins, inhibitors of cyclin-dependent protein kinases (CDKs), inhibitors of the onset of anaphase and proteins associated with the mitotic spindle. The specific and programmed degradation of all these regulatory proteins is essential for progression to the next stage of the cell division cycle. Pr Hershko and his laboratory are focussing on the biochemical mechanisms involved in the degradation of two important cell cycle regulators: cyclin B, the major mitotic cyclin, and the CDK inhibitor p27, whose degradation is required for the transition of cells from quiescence to the proliferating stage. They have found that cyclin B is targeted for degradation by the cyclosome (also called Anaphase-Promoting Complex or APC), a large complex that contains ubiquitin ligase activity specific for mitotic regulators.
Presently they are investigating the molecular mechanisms of the regulation of cyclosome activity in the cell cycle. The p27 CDK inhibitor is targeted for degradation by a different ubiquitin ligase complex, called SCF (Skp1-Cullin-F-box protein). They found that the SCF complex that targets p27 for degradation contains two proteins, Skp2 and Cks1, which have important roles in determining the specificity and regulation of its action. The elucidation of the mechanisms of ubiquitin-mediated degradation of cell cycle regulators may shed light on the pathogenesis or treatment of cancer, which is caused by uncontrolled cell proliferation.
Nobel Prize in Chemistry 2004
"for the discovery of ubiquitin-mediated protein degradation", jointly with Aaron Ciechanover and Irwin Rose.
Sudakin V., Ganoth D., Dahan A., Heller H., Hershko J., Luca F.C., Ruderman J.V. and Hershko A. (1995). The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol. Biol. Cell; 6, 185-198.
Carrano A., Eytan E., Hershko A. and Pagano M. (1999). SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nature Cell Biol.; 1, 193-199.
Ganoth D., Bornstein G., Ko T. K., Larsen B., Tyers M., Pagano M. and Hershko A. (2001). The cell cycle regulatory protein Cks1 is required for the SCFSkp2-mediated ubiquitinylation of p27. Nature Cell Biol.; 3, 321-324.