Irwin Allan Rose (1926–2015) Established Role of Ubiquitin in the Destruction of Cellular Proteins

COMMENT OBITUARY Irwin Allan Rose (1926–2015) Established role of ubiquitin in the destruction of cellular proteins.

rwin Allan Rose (Ernie) described in detail the various helped to elucidate how cells mechanisms and steps involved identify damaged proteins in the pathway — by adding Iand break them down into their certain stimulants and toxins, constituent amino acids. His such as inorganic phosphate and discoveries led to the develop- methylene blue. ment of ‘proteasome inhibitors’, In 1979, Rose was elected drugs used to treat certain types to the US National Academy of cancer. of Sciences for his studies on Rose, who died on 2 June, enzyme mechanisms. In fact, in CHASE CANCER CENTRE ARCHIVES FOX was born in 1926 in Brooklyn, many ways, his three decades of New York, where his father ran a experience had prepared him flooring business. Rose attended for the complexities of ubiquitin Washington State College in enzymology — a reminder of the Pullman and after a brief period value of pursuing basic science. in the US Navy during the In 2004, he shared the Nobel Second World War, he com- Prize in Chemistry with one of pleted a bachelor’s degree at the us (A.H.) and Ciechanover for University of Chicago in Illinois the ubiquitin work. in 1948. In 1952, he obtained a Ernie was so brilliant that doctorate in biochemistry from people did not always under- Chicago. stand his ideas, and were a little After two years of postdoc- afraid of him. People were also toral work, Rose became a faculty often apprehensive of interact- member of the Yale School of ing with him because he could Medicine’s biochemistry depart- be very critical, and did not ment in New Haven, Connecticut. While at Although Rose is best known for his hesitate to voice his judgements. But he was Yale, he met and married Zelda Budenstein, contribution to the ubiquitin field, he had incredibly generous in collaborations, a rare a graduate student in his department. Then, established himself as a leader in the study phenomenon in science today. in 1963, he moved to the Fox Chase Cancer of enzyme mechanisms long before. In the He always downplayed his contributions Center in Philadelphia, Pennsylvania, where late 1950s, for instance, he had been among to the ubiquitin field. He wrote an autobio- he spent most of his career. the first to attach radioactive compounds graphical article for Protein Science in 1995, By the mid-1970s, scientists had discov- to track the fate of metabolites in cellular in which the word ‘ubiquitin’ is not even ered that a certain protein — which came pathways. By radiolabelling precursors of mentioned; in conversations, he described to be known as ubiquitin — occurred in DNA, he showed in his PhD studies that the his role in the ubiquitin story as being merely numerous tissues and organisms, but its nucleotide cytidine is directly incorporated supportive. In fact, Ernie’s input of ideas, function was unknown. In the latter part into DNA, and that the reduction of cytidine inspiration and helpful criticism were essen- of the decade, in collaboration with one of to deoxycytidine is a necessary step in DNA tial for the discovery of the ubiquitin system us (A.H.) and biologist Aaron Ciechanover, synthesis. and for the delineation of some of the main Rose began to investigate this protein. By Later on at Yale, he investigated how enzyme reactions in the pathway. studying ubiquitin in reticulocytes — imma- enzyme mechanisms depend, in part, on After Ernie retired, he kept coming up ture red blood cells, which are simpler to use the spatial arrangement of the atoms that with bright ideas about problems such as the than other cells — we worked out that it was make up both the substrate and the enzyme origin of life, and more recently, about how crucial to protein degradation. This was the molecule, focusing on processes involved in to solve global warming. He will be missed. ■ first step to discovering that proteins bound carbohydrate metabolism. to ubiquitin are broken down by protein At Fox Chase, he became interested in Keith Wilkinson is professor and vice- complexes called proteasomes and the frag- the regulation of glycolysis, the breakdown chair of biochemistry at Emory University, ments recycled into new proteins. of glucose, in red blood cells. Many cancer Atlanta, Georgia, USA. He met Irwin Rose The discovery of ubiquitin-based protein cells are more dependent on glycolysis than in 1977 when he arrived in Philadelphia as degradation has since shed light on various are normal cells — a phenomenon called the a postdoctoral fellow. Avram Hershko is diseases, such as cancer, which can occur Warburg effect, after the biochemist Otto professor of biochemistry at the Rappaport when the pathway is defective. The work Heinrich Warburg. Working out why was of Faculty of Medicine, Technion-Israel has also led to the development of several key interest to the cancer-research commu- Institute of Technology, Haifa, Israel. He drugs that are used to treat blood cancers. nity at the time. Rose’s work on the enzyme met Rose during a sabbatical year in Rose’s These act by disrupting the protein-disposal hexokinase showed that its phosphorylation laboratory in Philadelphia in 1977. system; the cancer cells are killed when the of one of the carbon atoms in glucose is the e-mail: [email protected]; damaged proteins pile up. main rate-limiting step in glycolysis. Rose [email protected]