Cyclin and Genetics - Avram Hershko and the Degradation of Cyclin

After Tim Hunt’s discovery of cyclin in 1982 and the explosion of our understanding of the cell cycle that followed, one large question remained - how was cyclin degraded in the cell? Researchers knew from Hunt’s work that the levels of cyclin in the cell fluctuate, appearing and disappearing throughout the cell cycle. That meant that something must be degrading the cyclin at specific points during the cell cycle, but what that something was was not known until 1991.

Avram Hershko is an Israeli biochemist, who came to the MBL in the early 90s and outlined the degradation of the protein cyclin. For much of the history of the study of proteins, it was thought that proteins were stable, rarely degrading (Varshavsky, 2006). In 1942, biochemist Rudolf Schoenheimer showed that in fact, proteins are almost constantly overturned in the body - synthesized, used, and degraded quickly and frequently (Schoenheimer, 1942). However, after Shoenheimer showed that proteins do degrade, the next question became what degraded proteins? That question was answered far before attention was turned to the degradation of cyclin.

Ubiquitin is a regulatory protein that has been found in almost every tissue of eukaryotes. Ubiquitin was identified for the first time by immunobiologist Gideon Goldstein and his research team (Goldstein, 1975). When Goldstein identified ubiquitin, it was clear that it was important given its prevalence in different tissues and organisms, but its purpose was unknown. At the time, Avram Hershko and his graduate student Aaron Ciechanover identified a protein they named ATP-dependent proteolytic factor 1, but is now known as ubiquitin after being identified as the same molecule (Nature Cell Bio, 2004). Along with collaborator Irwin Rose, Hershko and Ciechanover showed that when ubiquitin, attached to a given protein, that protein was degraded by the cell (Hershko, 1999: 1571). In 1980, they proposed that ubiquitin may target or label proteins for degradation (Hershko, 1999: 1571). Over the next several years, Hershko, Rose, and Ciechanover carefully laid out the steps by which ubiquitin attaches to proteins, thus marking them for degradation, after which the ubiquinated protein is degraded by the body (Varshavsky, 2006).

Then in 1984, a year after Tim Hunt discovered cyclins and their disappearance and reappearance in the cell throughout the course of the cell cycle, Ciechanover and two collaborators suggested that cyclins were degraded via the ubiquitin pathway laid out by Hershko and others (Ciechanover, 1984). In 1991, Hershko traveled to the MBL in order to determine if cyclins were degraded by the ubiquitin mediated protein degradation pathway (Nobel Prize, 2004). While at the MBL, Hershko used the same animal model that Ruderman used twenty years before - the clam oocyte - due to the faithful representation of cell cycle related events (Nobel Prize, 2004).

In 1991, Hershko published an outline of the molecules and processes necessary for the degradation of cyclins by the ubiquitin pathway (Hershko, 1991). Independently, former MBL researchers Andrew Murray and Marc Kirshner along with Michael Glotzer outlined the same pathway (Glotzer, 1991). That discovery by Hershko and others proved to be important for future cancer research and also formed the last piece of the puzzle of cell cycle regulation in cells. By 1991, the general processes were understood, though as of 2015, many of the molecules involved have yet to be identified.