Prof. Dr. Avram Hershko, M.D., Ph.D. & Prof. Dr. Aaron Ciechanover
for the Detection and Elucidation of the Ubiquitin-System
As its name implies, ubiquitin is a protein that is found in all nucleated cells. It is present in yeasts, fish, insects and man; in all these organisms the molecule is practically identical. It is made up of 76 amino acid residues. Yeast ubiquitin differs from the human molecule only by three residues – although approximately one billion years of evolution separate these two organisms. Ubiquitin is thus the most highly conserved protein known - a reliable indicator of a particularly important cellular function. What is known of the function of ubiquitin? All proteins are subject to synthesis and degradation. Two systems are responsible for intracellular protein degradation: the non-specific waste-disposal via cellular dust-bins (lysosomes), and the specific energy-dependent degradation in cytosolic proteasomes. Hershko and Ciechanover were the first to discover the energy-dependent degradation process in 1978 – a very unexpected finding because protein hydrolysis is an exergonic process, which should by definition pass without energy consumption. If cells invest energy for the purpose of degrading proteins, it is clear that the removal of these compounds is an important biological task. Hershko and Ciechanover showed that proteins designed to be degraded via the energy-dependent pathway bear a specific marker – a heat labile tag, which they called ubiquitin. Ubiquitin is bound to the proteins doomed for degradation by the energy- dependent action of three enzymes (E1, E2 and E3). Often more than one ubiquitin molecule may be bound to a target protein; sometimes as many as 50 are attached. The tagged proteins are recognized and degraded by professional protein degrading organelles, the proteasomes – a process which again consumes energy provided by ATP. The ubiquitin molecule survives intact and is recycled for further use. Energy is thus consumed for both sorting out the protein targets and for their destruction.
Which proteins are degraded by such costly a process? They are essentially of two types:
a. defective proteins. Cellular proteins serve either structural or functional purposes. Both kinds may exhibit defects due to flawed synthesis or folding – with potential grave consequences. Sorting out and eliminating defective proteins thus represents a cellular quality control system.
b. proteins involved in short-lived regulatory processes. The synthesis of such proteins is switched on at demand, and the proteins are quickly degraded by ubiquitination once their job is done. Cell cycle regulatory proteins are prototypes of such molecules. Cells enter and pass through the cell cycle in response to a variety of messenger substances including cyclins – which activate cells to enter individual cell cycle phases, and inhibitory messengers – like protein p27 – which arrest the cell cycle at certain points. To allow the passage through the whole cell cycle, activators and inhibitors must be synthesized and degraded (by ubiquitination!) in a tightly controlled fashion. This mechanism is profoundly important since uncontrolled cell cycle passage may lead to uncontrolled cellular proliferation, i.e. cancer. Some observations indicate that the ubiquitin system may be involved in carcinogenesis for example; carcinoma of the cervix is caused by chronic infection with certain human papilloma viruses. These viruses eliminate an important cell cycle inhibitor by „non-physiological“ activation of the ubiquitin system, resulting in incessant cell cycle stimulation. Other important regulatory functions of the ubiquitin system relate to transcription factors that control development and differentiat on, regulation of the immune system, of ion channels, neuronal functions and a plethora of further mechanisms.
Obviously, disturbances of the ubiquitin system, which is involved in so many essential biological functions, are bound to cause a multitude of disease states. Carcinogenesis has been mentioned above; severe neurological disease is another consequence, such as Huntington chorea (deposits of the ubiquitinated proteins huntingtin and ataxin) or Alzheimer disease (accumulation of ubiquitin conjugates of the t-protein), and specific forms of arterial hypertension.
Ubiquitin-mediated protein degradation is one of the biologically most important cellular processes. We owe its discovery, characterization and the elucidation of the underlying mechanisms to the team of Hershko and Ciechanover.
Prof. Dr. Avram HERSHKO, M.D., Ph.D.
|1937||Born in Karcag, Hungary|
|1950||emigrated to Israel|
|He started studying medicine at the Hadassah and the Hebrew University in Jerusalem and in 1964, he graduated to M.D. In 1969 he graduated to Ph.D. at the same university.
Between 1969 ánd 1971, he worked as Post-Doc at theUniversity of California, San Francisco, Medical Center, in the laboratory of Gordon Tomkins.
From 1971 to 1973, he taught as Senior Lecturer at the Technion - Israel Institute of Technology in Haifa; in1973, he was appointed Associate Professor and in1978, Full Professor.
|1987||Weizmann Prize for Exact Sciences|
|1994||Israel Prize in Biochemistry and Medicine|
Prof. Dr. Aaron CIECHANOVER
|1947||Born in Haifa, Israel|
|He did his studies in medicine at the Hadassah and Hebrew University in Jerusalem and earned his M.D. in 1974.
In 1981, he graduated to Ph.D. at the Technion in Haifa.
From 1981 to 1984, he was Post-Doctoral Fellow at the MIT in Cambridge, Massachusetts, working with Harvey Lodish.
In 1984 he took a position as Senior Lecturer at the Technion in Haifa; in 1987, he was appointed Associate Professor and in 1992, Full Professor.
|1985-1990||Research Carreer Development Award, Israel|
|1988-1989||American Cancer Society EleanorRoosevelt Memorial Fellow|