MERIT Award Recipient: Robert Tjian, Ph.D.
SV40 Tumor Antigen
The Tjian laboratory has been engaged in the biochemical isolation, molecular cloning, genetic analysis and structural determination of a large family of human regulatory proteins called transcription factors. The transcriptional apparatus represents the core molecular machinery responsible for decoding and expressing the genome of all organisms. Over the past 25 years they have used a combination of biochemistry and molecular genetics to piece together a relatively detailed but as yet incomplete picture of this remarkably ornate, highly regulated and essential process of gene selective RNA synthesis.
They began their studies with the isolation of the first DNA binding transcription factor derived from animal cells, the SV40 tumor antigen. Using a powerful biochemical complementation strategy and reconstituted transcription reactions, they discovered that approximately 100 distinct proteins must assemble on specific DNA templates to initiate the synthesis of RNA in multi-cellular organisms. As it turns out, many oncogenes and tumor suppressors are themselves members of the transcription factor family. Consequently, understanding how sequence-specific DNA binding proteins such as the SV40 T-antigen, the human Sp1 protein and the proto-oncogene Jun/Fos work as promoter recognition factors represents a basic level of knowledge that may help the development of novel anti-cancer therapies.
Research in the Tjian lab is aimed at the biochemical characterization and molecular dissection of the highly orchestrated interplay of DNA binding proteins, general transcription complexes, co-activators, and chromatin remodeling co-factors. In addition to this remarkable level of combinatorial complexity, a number of studies suggest an unexpectedly high degree of gene-specific and cell type-selective functions. The recent discovery of tissue-specific components of what had previously been thought to represent a largely invariant and universal transcriptional apparatus has presented the cancer research community with opportunities to identify potential novel therapeutic targets for drug intervention. By taking advantage of the rapidly evolving knowledge of how specific DNA binding proteins work to regulate transcription and gene expression in humans, the Tjian laboratory hopes to develop more specific and effective therapeutic agents against cancer as well as other diseases.