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experiments, it was in every one. Then theyfound it in every type of tissue they lookedat. The stuff was in pigs, guinea pigs, mice,plants, insects, people, even yeast. The onlyplace it didn’t show up was in a few primitivemicroorganisms.In 1974, the scientists introduced their newprotein—aptly named “ubiquitous immunopoieticpolypeptide” (later shorthanded to“ubiquitin”)—in a paper in the Proceedings ofthe National Academy of Sciences. Then theypromptly abandoned it because it wasn’t thethymic hormone they sought. An aside at theend of the PNAS paper noted that the proteinoccurs so universally it must be an “integralfeature” of nearly all living things.Ubiquitin would not resurface as a researchtopic until five years later when two Israeli scientists,collaborating with an investigator atthe University of California, Irvine, set out tofind the explanation for a recently discoveredphenomenon known as “energy dependentprotein degradation.”Researchers in the 1970s had noted thatwhenever there was a burst of amino acidsreleased inside cells, there was a correspondingconsumption of energy. Looking for whatwas using the energy—figuring it was chewingup proteins and releasing amino acids inthe process—the investigators turned up whatthey thought was a newly discovered protein.It seemed to be able to degrade other proteinsunder certain conditions. Upon talkingto their colleagues and searching the scientificliterature, they realized what they’d comeupon was ubiquitin.In a flurry of studies in the early 1980s,researchers showed that ubiquitin does notdegrade proteins directly but rather flagsthem for demolition by a long, hollow moleculecalled a proteosome. It takes at least fourubiquitin tags for a protein to be targetedfor destruction. As the protein is degradedby the proteosome, the ubiquitin moleculesare liberated, free to search out potential newtarget proteins for disposal.And scientists made another importantdiscovery: Ubiquitin mostly tags abnormalproteins for destruction. Unfortunately, ittook a few decades before the full implicationof this latter finding was appreciated. As oneretelling of those events recently noted, ubiquitinresearch “was little more than a backwaterof biochemistry studied by a handful oflaboratories” for many years to come.Ubiquitin’s status as a topic of researchinterest did not change dramatically until2003, when the Israelis and one of theirAmerican collaborators were given the LaskerAward for their work on the ubiquitinproteosomepathway. A year later, the twoIsraelis and another American colleague wereawarded the Nobel Prize for Chemistry.Scientists now recognize ubiquitin as amaster regulator of a broad host of cellularprocesses. They suspect that alterations in theubiquitin-proteosome protein-disposal systemfactor into a number of diseases, includingneurological conditions, liver diseases, eyediseases, and a variety of cancers.Just as the greater scientific communitywas beginning to recognize the importanceof the ubiquitin-proteosome pathway, YongWan, now a PhD assistant professor of cellbiology and physiology at the University ofPittsburgh School of Medicine, was arrivingat Pitt after completing his postdoctoral trainingat Harvard University.At Harvard, Wan had worked for cellbiologist Marc Kirschner. One of the first tounderstand the importance of the pathwayfor normal cell functions in the mid-1990s,Kirschner and his lab had discovered a ubiquitinligase known as anaphase-promoting complex(APC), which is involved in making surethat cells divide properly. Kirschner assignedWan to work on APC, and Wan broughtthat project with him to Pitt in 2003, wherehe was one of just a handful of investigators(including the medical school’s dean, ArthurS. Levine) interested in this relatively new areaof inquiry.Today, Wan’s lab is one of several dozenat Pitt delving into some aspect of this multifacetedenzyme. Others are investigatingubiquitin’s role in neurological conditions,including Alzheimer’s, as well as xerodermapigmentosa, an inherited disease that makespeople extremely sensitive to natural sunlightwhile putting them at high risk for skincancer. The disease can inhibit the effectsof radiation therapy and chemotherapy ontumors, promote the growth and proliferationof cancers, and influence circadian rhythms.Wan has several large grants from theNational Cancer Institute and the AmericanCancer Society to not only investigate APC’srole in normal cell division but also to look atwhether environmental factors, such as chemicalsor radiation, might damage APC or causeother alterations in its activity.“The major role of APC is to control theseparation of chromosomes during cell divisionby ungluing the chromosome strands.Deregulation of this separation process usuallyresults in catastrophic alterations in the shapeand number of chromosomes in a cell, whichis a hallmark for many types of tumor cells,”Wan explains.His laboratory, based at the University ofPittsburgh Cancer Institute, also looks intoubiquitin’s role in stem cell maturation. Wanbelieves the ubiquitin-proteosome system actslike a licensing agency, allowing stem cells tobecome specific types of cells, such as muscleor liver cells, by orchestrating the degradationof all but one type of signal.Others at Pitt have suggested that ubiquitininfluences how we perceive the world.The laboratory of Yong Tae Kwon, aPhD assistant professor in the Center forPharmacogenetics in the School of Pharmacy,explores a pathway in the ubiquitin-proteosomesystem called the N-end rule pathway.Wan believes the system acts like a licensing agency,allowing stem cells to become specific types of cells.Takafumi Tasaki, a PhD and a memberof the Kwon lab, has uncovered indicationsthat the pathway is involved in regulatingsensations in mice. “It is only a hypothesisright now, but we think it may be importantin regulating synaptic transmission in sensorysystems, including smell, taste, vision, andhearing,” he says.Others in the Kwon lab have shown thatthe enzymes in the N-end rule pathway playessential roles in heart formation, blood vesseldifferentiation, male reproduction, chromosomestability, neural tube development,muscle protein degradation, fat metabolism,and blood development.Although it is hard to predict where all ofthis research will lead and when it will turninto treatments for major diseases, it is safe tosay that ubiquitin research is likely to becomemuch more, well, ubiquitous in the comingyears at Pitt.“When I arrived here a little more thanfour years ago, there was not a lot of researchin ubiquitin going on,” recalls Wan. “But now,research in this area is booming.” ■SUMMER 2007 11