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Robert G. Roeder

Robert G. Roeder (born June 3, 1942 in Boonville, Indiana, United States) is an American biologist. He is the recipient of the Gairdner Foundation International Award in 2000 and the Albert Lasker Award for Basic Medical Research in 2003. He currently serves as Arnold and Mabel Beckman Professor and Head of the Laboratory of Biochemical and Molecular Biology at The Rockefeller University.

Biography

Roeder was born in Boonville, Indiana, USA in 1942. He received his B.A. summa cum laude in chemistry from Wabash College and his M.S. in chemistry from the University of Illinois. He received his Ph.D. in biochemistry in 1969 from the University of Washington, Seattle, where he worked with William Rutter. He did postdoctoral work with Donald D. Brown at the Carnegie Institution of Washington, in Baltimore, from 1969 to 1971. He was a member of the faculty at Washington University School of Medicine in St. Louis from 1971 to 1982, when he joined The Rockefeller University. In 1985, he was named Arnold and Mabel Beckman Professor. He was elected as a member of the National Academy of Sciences in 1988 and the American Academy of Arts and Sciences in 1995, and a foreign associate member of the European Molecular Biology Organization in 2003.

Scientific Research

One of the biggest questions in biology is how cells control or regulate transcription, the process by which genes are copied into RNA for translation into proteins, and how this process breaks down in certain diseases such as cancer. The answer ultimately may lead to new drugs that selectively switch genes on or off for the treatment of not only cancer but also heart disease, Alzheimer's disease, AIDS and any other medical condition in which normal gene activity is disrupted.

Dr. Roeder's broad objectives are to understand the specific regulatory events that control these processes, as well as more fundamental aspects of transcription activation and repression mechanisms. To this end, his specific objectives are to determine the nature and mechanism of action of both the general transcription machinery that is commonly used by all genes and the gene- and cell-type-specific factors that directly regulate target genes in response to various growth, developmental and stress stimuli.

His lab's multipronged experimental strategy begins with the use of a biochemical tool called the cell-free system, pioneered by Dr. Roeder, that allows researchers to recreate the essence of transcription in a test tube with cloned genes and cellular extracts. They then biochemically dissect these systems, purify and clone the individual factors and study the structure, function and regulation of these factors by a combination of biochemical and genetic (i.e., transgenic, knockout and knockin mice) analyses.

The actual transcription of protein-coding genes is mediated directly by RNA polymerase II and a number of common initiation factors (TFIID, TFIIA, TFIIB, TFIIE, TFIIF and TFIIH) that form functional preinitiation complexes on promoters via an ordered assembly pathway that begins with recognition of common core promoter elements (notably the TATA box and initiator elements) by the multisubunit TFIID.

These factors — comprising the general transcription machinery — represent the ultimate targets of the various gene-specific factors. However, despite the specificity intrinsic to the gene-specific transcriptional regulatory proteins, the complexity of the general transcription machinery (about 44 distinct polypeptides), and documented physical interactions among these components, other “cofactors” have been found essential for functional communication between the gene-specific activators/repressors and the general transcription machinery on specific target genes.

Dr. Roeder's work is now heavily focused on these cofactors (both coactivators and corepressors), many of which are structurally complex. They include cofactors (e.g., multisubunit histone acetyltransferase, methyltransferase and ubiquitination complexes) that alter the structure of the natural chromatin template, cofactors (e.g., the 30-subunit Mediator complex and negative regulators NC-2 and Gdown-1) that act directly on the general transcription machinery, and a variety of gene- and/or activator-specific factors (e.g., the B cell-specific OCA-B and the inducible PGC-1 implicated in energy metabolism). Current activities focus on transcriptional activators (and corresponding genetic regulatory pathways) important for: homeostasis (nuclear receptors such as thyroid hormone receptor, estrogen receptor, estrogen-related receptor and peroxisome proliferation-activated receptor); lymphoid/myeloid cell differentiation and malignancy (OCT-1/2, NFKB and OCA-B; E2A and leukemogenic fusion proteins E2A-HLA and E2A-Pbx1; AML1 and the leukemogenic AML1-ETO fusion protein; mixed lineage leukemia factor [MLL-1] and its leukemogenic fusion partners); and DNA damage responses (tumor suppressor p53 and related family members).

Apart from detailing the mechanisms by which specific target genes are activated by individual transcriptional activators and essential cofactors, the Roeder laboratory also is interested in determining differential usage of cofactors by different activators or by the same activator in different cell types or on different target genes and, especially, how variations in cofactors can dictate cell fate (e.g., growth arrest versus apoptosis in p53-dependent DNA damage responses).

Major Discoveries

  • 1969-1977: In 1969, as a graduate student at the University of Washington, Roeder discovers that three enzymes, called RNA polymerases, directly copy DNA in animal cells. As a professor at Washington University in St. Louis, he goes on to show that these enzymes, referred to as Pol I, II and III, recognize and copy distinct classes of genes.
  • 1977-1979: Roeder develops cell-free systems to better study transcription. Composed of the purified RNA polymerases and components extracted from cell nuclei, the systems allow researchers to recreate transcription in a test tube in a way that faithfully mimics the real process in cells.
  • 1980: The development of cell-free systems leads to the identification of complex sets of proteins called accessory factors that are essential for each individual RNA polymerase (Pol I, II and III) to "read" specific target genes.
  • 1980: Roeder identifies the first mammalian gene-specific activator, called TFIIIA. TFIIIA and similar proteins bind to specific DNA sequences and enhance the reading of corresponding target genes. Repressors perform the opposite task by inhibiting a gene's activity.
  • 1990s: A decade of research culminates with the discovery of coactivators, large protein complexes that provide a bridge between the activators and repressors and the RNA polymerases and other components of the general transcription machinery.
  • 1991: Roeder's laboratory demonstrates that coactivators can be ubiquitous, monitoring many genes in a variety of cells, or specific to one particular cell type. Roeder and colleagues introduce the concept of cell specificity after they demonstrate that the coactivator OCA-B, the first cell-specific coactivator, discovered by Roeder in 1991, is unique to immune system B cells.
  • 1996: Roeder's laboratory discovers the major conduit for communication between gene-specific activators and the general transcription machinery in animal cells: a giant coactivator (TRAP/SMCC) that consists of about 25 different protein chains and is referred to as the human mediator after its counterpart in yeast.
  • 2002: Roeder and colleagues show that a single component of the mediator is absolutely essential for the formation of fat cells — a finding that may one day contribute to new treatments for diabetes, heart disease, cancer and other conditions in which the fat-making process breaks down.

Highly Cited Papers

  • 1. Dignam, J. D., Lebovitz, R. M., and Roeder, R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res., 11: 1475-1489, 1983. Times Cited: 9,404
  • 2. Gu, W. and Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell, 90: 595-606, 1997. Times Cited: 1,184
  • 3. Sawadogo, M. and Roeder, R. G. Interaction of a gene-specific transcription factor with the adenovirus major late promoter upstream of the TATA box region. Cell, 43: 165-175, 1985. Times Cited: 1,046
  • 4. Dignam, J. D., Martin, P. L., Shastry, B. S., and Roeder, R. G. Eukaryotic gene transcription with purified components. Methods Enzymol., 101: 582-598, 1983. Times Cited: 750
  • 5. Roeder, R. G. and Rutter, W. J. Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms. Nature, 224: 234-237, 1969. Times Cited: 726

Honors and Awards

Current Members of the Roeder Laboratory

  • Janice M. Ascano, Postdoctoral Associate
  • Carmen-Gloria Balmaceda, Laboratory Manager
  • Debabrata Biswas, Postdoctoral Fellow
  • Stephen Burley, Member of the Adjunct Faculty
  • Wei Chen, Research Associate
  • Wei-Yi Chen, Postdoctoral Fellow
  • Zheng-Yuan Fu, Research Assistant
  • Mohamed Guermah, Research Associate
  • Satoshi Iida, Postdoctoral Associate
  • Hao Jiang, Postdoctoral Fellow
  • Miki Jishage, Postdoctoral Fellow
  • Jaehoon Kim, Postdoctoral Fellow
  • Shannon M. Lauberth, Postdoctoral Fellow
  • Xiangdong Lu, Postdoctoral Fellow
  • Sohail Malik, Research Associate Professor
  • Olga Matthew, Laboratory Helper
  • Neri Minsky, Postdoctoral Fellow
  • Tomoyoshi Nakadai, Postdoctoral Associate
  • Takahiro Nakayama, Postdoctoral Associate
  • Adam Nock, Research Assistant
  • Jeong Hyeon Park, Postdoctoral Fellow
  • Xiaodi Ren, Research Associate
  • Robert G. Roeder, Arnold and Mabel Beckman Professor
  • Toru Sengoku, Postdoctoral Fellow
  • Miho Shimada, Postdoctoral Associate
  • Xiao-Jian Sun, Postdoctoral Fellow
  • Zhanyun Tang, Postdoctoral Fellow
  • Zhu Xue, Research Assistant
  • Qi-Heng Yang, Postdoctoral Fellow
  • Orlee D. Zorbaron, Office Administrator

Prominent Alumni of the Roeder Laboratory

References

External links

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