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조박
조박(Park F. Cho) 저자 이메일 보기
McGill University
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조회 4158  인쇄하기 주소복사 트위터 공유 페이스북 공유 
A New Paradigm for Translational Control: Inhibition via 5''-3'' mRNA Tethering by Bicoid and the eIF4E Cognate 4EHP
1. 논문관련 분야의 소개, 동향, 전망을 간단히 설명

Since joining the laboratory of Dr. Nahum Sonenberg, at McGill University, in 2001 as a Graduate student, I strived to understand how translation (protein synthesis) is controlled in eukaryotes. Because all cellular function requires protein activity, any mechanistic insight into how proteins are synthesized will have profound consequences in our understanding of the biology of cell.

Translation rates are often controlled at the initiation phase, a multi-step process involving the recruitment of the 40S small ribosomal subunit to the 5' end of an mRNA and culminate in the positioning of the ribosome at the initiation codon. Recognition of the mRNA 5' cap structure (m7GpppN, where N is any nucleotide) by eukaryotic initiation factor (eIF) 4F (composed of three subunits: eIF4E, eIF4A and eIF4G) facilitates this process. The ability of eIF4F complex to bind to the Cap structure, as a result of the eIF4E:Cap interaction, is of particular importance. As such, eIF4E has emerged as a major target of translational regulatory mechanisms.

Early embryo development in eukaryotes requires the activity of various maternal determinants called morphogens, whose spatial and temporal expressions are tightly regulated at the level of translation. Positional information embedded within each morphogen is important for the establishment of polarity and subsequent organization of both antero-posterior and dorso-ventral axes of an embryo. For instance, in Drosophila, when maternal caudal (cad) is allowed to accumulate inappropriately in the anterior half of an embryo, anterior segmentation is blocked. Hence, precision of the cad expression domain is critical for normal development.

An eIF4E-related protein called eIF4E-Homologous protein was first described by a post-doc in our lab in 1998. However, the function, if any, of 4EHP in translation has been elusive, since it does not interact with any known initiation factors. In order to elucidate its biological function, we employed the power of Drosophila genetics. In our report, we show that the Drosophila 4EHP homolog (d4EHP) interacts with a protein called Bicoid to inhibit the anterior translation of maternal cad mRNA. Simultaneous interaction of d4EHP with the cap and Bicoid results in mRNA circularization and renders cad mRNA translationally inactive. This example of cap-dependent translational control that is not mediated by eIF4E defines a new paradigm for translational inhibition involving tethering of the mRNA 5' and 3' ends.

2. 연구과정에서 생긴 에피소드

During the course of this study, my brothers (Andrew and Ian, both co-authors) and I often had to work very late at night (usually till 1 am). This usually meant that we had no choice but to take the last bus and subway ride home. Since McGill University medical building is located at the top of a mountain, we always had to run down the mountain to make sure that we catch this very last bus/subway. Although it is quite an enjoyable run during summer time, running down the mountain in cold/icy Montreal winter gave a whole new meaning to the word "running"!!!

As many of you may already know, doing research can be very frustrating. This is why you need a lot of patience and an effective stress coping strategy. For us three brothers, when an experiment goes wrong and stress accumulates, we would take our hockey sticks and play a mini-hockey game (5-10 min) in the corridors of the institute.

3. 본 연구가 이루어진 기관 또는 연구소에 관한 소개를 부탁드립니다.

Founded in 1829 by James McGill, a Scottish immigrant who prospered in Montreal, McGill University is one of Canada's premier institutes of higher learning. Located in the heart of cosmopolitan city of Montreal, McGill University is world renown for its achievements in Medical and Basic sciences. Nobel Prize winners Ernest Rutherford (Chemistry, 1908), Frederic Soddy (Chemistry, 1921), Otto Hahn (Chemistry, 1944), Andrew Victor Schally (Medicine, 1977), Val Fitch (Physics, 1980), David Hubel (Medicine, 1981) and Rudolph Marcus (Chemistry, 1993), and towering medical pionners such as William Osler (Father of Modern Medicine) who became the first professor of Medicine at Johns Hopkins, Donald O. Hebb, Wilder Penfield, Brenda Milner and Ronald Melzack are amongst the most famous members of McGill community.

My supervisor Dr. Nahum Sonenberg, a James McGill Professor of Biochemistry, Canadian Institute of Health Research (CIHR) Distinguished Scientist and a Howard Hughes Medical Institute (HHMI) International Scholar, is world renown for his pioneering work in eukaryotic protein synthesis. While he was a post-doc at Aaron Shatkin's lab at the former Roche Institute (New Jersey, USA), he identified the role of the mRNA 5' Cap-binding protein eIF4E in translation. Subsequently, he was the leader of a research group that identified the internal ribosome entry site (IRES) in poliovirus and showed that eIF4E is one of biology's most potent oncogene. For his seminal contributions, he was recently awarded the Robert L. Noble prize from the National Cancer Institute of Canada (NCIC) and the Killam award from the Canadian Council of Art and Sciences. Dr. Sonenberg's laboratory is affiliated with the Department of Biochemistry and McGill Cancer Centre.

4. 연구활동 하시면서 평소 느끼신 점 또는 자부심, 보람

Throughout this study, I always felt proud to have had the opportunity to work with my brothers in one of the top laboratory in the world. In addition, I am especially grateful that my project worked so well in such a short period of time.

5. 이 분야로 진학하려는 후배들 또는 유학준비생들에게 도움이 되는 말씀을 해 주신다면?

Because today's biomedical research is moving at lightening speed, opportunities are plentiful. For those who are hoping for a great graduate student career, I must emphasize that choosing the right research advisor takes precedence over everything else such as fame of the university and the city in which it is located. Secondly, make sure that you and your advisor have common goals and work ethics. In this regard, use the interview process to learn as much as possible about a professor; making sure to talk to resident graduate students!

6. 연구활동과 관련된 앞으로의 계획이 있으시다면?

After graduating late this fall, I intend to continue doing research in basic science by seeking a joint post-doc/M.D. position. I am especially interested in developing new methods that allows scientists to accurately measure/observe biological phenomenon.

7. 다른 하시고 싶은 이야기들....

I would like to express my sincerest gratitude to my family for their unwavering love and support, and to those who value my work. Thank you!


  Received for article June 8, 2005
 등록일 2005-06-08
Category: 생물학관련 모든분야
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