For over 30 years he has worked in the field of RNA biology where he cloned cDNAs encoding several members of the RNA recognition motif (RRM) family RNA-binding proteins and first demonstrated its binding specificity as a single unit domain of the U1 snRNP-70K protein. He derived clones of the ELAV/HuB protein and discovered that this family of RRM proteins binds to G/AU-rich elements that reside in the 3’ UTRs of mRNAs encoding c-myc, c-fos, GM-CSF and other cytokines and protooncoproteins. In addition, his lab first demonstrated that ELAV/Hu proteins stabilize these mRNAs and can activate their translation. More recently, Keene demonstrated coregulation of early response gene mRNAs by ELAV/Hu and other RNA-binding proteins, a series of findings that led to the theory of Posttranscriptional RNA Operons. This concept of coordinated gene expression has been widely confirmed in many biological systems in numerous laboratories using several independent techniques. Keene served previously as chairman of the Department of Microbiology at Duke University Medical Center and director of basic sciences for the Duke Comprehensive Cancer Center. In 1999, Keene founded the Duke Center for RNA Biology where he was its first director.

The TIA and TIAR RRM proteins discovered by Anderson are major regulators of the stability of mRNAs encoding cytokines and chemokines. One of the most significant findings from the Anderson lab that were made by Kedersha and Anderson is the finding that stress granules, which form following the activation of oxidative stress using compounds like arsenite. Stress granules have been found to contain many different RNA binding proteins in addition to translationally silenced mRNAs. Interestingly, the TIA protein plays a critical role in forming stress granules because depletion of TIA from cells prevents the formation of stress granules. An interesting observation by the Anderson lab is that TIA contains a prion domain that constitutes an aggregated core that allows stress granules to form.

Dr. Blackshear was previously an investigator or the HHMI while a professor at Duke University Medical Center where he still holds an adjunct appointment in the Department of Biochemistry. In addition to many seminal contributions in the field of signal transduction, Blackshear made a major discovery that the zinc finger protein, tristetraprolin (TTP) is an RNA binding protein that binds to AU-rich sequences in cytokine mRNAs, principally tumor necrosis factor alpha (TNF-α) and functions as a destablizer of these mRNAs. This discovery involved the creation of a knockout mouse in the gene encoding TTP, a protein believed at the time to be a transcription factor. The phenotype of these mice indicated that TNF-α levels increased dramatically. Blackshear and coworkers demonstrated unexpectedly that TTP regulated the stability of the TNF-α mRNA and was in fact not a transcription factor. Subsequently, Christoph Moroni, another invited speaker at this conference discovered a homolog of TTP called butyrate response factor (BRF1) has distinct expression but a similar function of destabilizing cytokine and chemokine mRNAs. Based on Blackshear’s work, many labs throughout the world have turned their research programs toward TTP because it is an important posttranscriptional regulatory protein in the immune system and other cell types.

Brewer developed the first in vitro RNA stability system while a postdoctoral fellow with Jeffrey Ross at the University of Wisconsin and used that system in his own lab to discover the RRM protein known as AUF1 or hnRNP-D. This protein occurs in several isoforms and some of them affect the stability of mRNAs that contain the AU-rich instability sequences known to occur in early response gene transcripts such as c-myc, cfos and others. It is interesting to note that this AU-rich or ARE sequence feature is common to many mRNAs that encode highly reactive growth regulatory proteins, and the ARE and the ARE-binding proteins are a major focus of this meeting. As noted above, the ELAV/Hu, TTP, BRF1, TIA and AUF1 RNA-binding proteins are of interest to the leading scientists at this conference, in part because of their implications for many diseases.

Gorospe is one of the youngest members of the organizing committee and has emerged as a highly productive scientific star in the field of RNA stability and translation. Dr. Gorospe is of latino origin and a native of Spain who trained in interferon biology before moving to the NIH. While Gorospe is an expert on RNA-protein interactions and has achieved an outstanding reputation in the field in recent years, her biological system of focus concerns mechanisms of genotoxic responses, oncogenesis and cell damage at the post-transcriptional level. She has made many seminal discoveries in this respect, among them the finding that the ELAV/HuR protein regulates the stability and/or translation of GADD45, p53, β-catenin and other important proteins involved in cell survival and apoptosis. In addition, she has pioneered genome-wide analysis of mRNA targets of RNA binding proteins including ELAV/HuR, TIA, TIAR and many others. Her most recent work demonstrated that ELAV/HuR activates translation of the mRNA encoding an aging-related protein, SIRT-1 via a mechanism of phosphorylation that affects the RNA-binding specificity of HuR. These findings demonstrate for the first time that RNA-protein interactions that affect the expression of early response gene transcripts involved in longevity are regulated post-translationally.

Dr. Port has worked for many years in the area of G protein coupled receptors such as β-adrenergic receptors. Many of the mRNAs encoding these proteins are regulated at the level of RNA stability. Port and coworkers have discovered many RNAbinding proteins associated with mRNAs encoding regulated cellular receptors. For example, Port has shown that the ELAV/HuR protein and the AUF1 protein regulates the stability of the β-adrenergic receptor in cardiac cells as well as in tumors. Dr. Port originated this conference series by organizing the first meeting in 2003 in Florence, Italy that was focused almost entirely on the ARE itself. The 2005 meeting in Arolla, Switzerland broadened the areas of RNA stability to include other cis regulatory elements besides the ARE and to other RNA-binding proteins involved in RNA stability.

 

 

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