Dr. Michael Carey's work attempts to understand the molecular details of how different human genes are turned on and off during disease.
One of the central themes to emerge in molecular biology over the last decade is that specific gene expression patterns are controlled by massive molecular machines termed transcription complexes. These complexes assemble over the regulatory region of a gene and control the specificity and activity of transcription. The complexes contain activators, co-activators and general transcription factors. Activators bind cooperatively to promoters and enhancers to assemble into nucleoprotein complexes called enhanceosomes. The enhanceosome recruits co-activators that then interact with general factors such as RNA polymerase, which carry out the catalytic process of transcription initiation and elongation.
Carey and his colleagues are particularly interested in a co-activator complex termed mediator and how it functions in an in vitro system on chromatin templates. They have identified interactions between mediator and chromatin remodeling factors and between mediator and general transcription factors. Carey believes that the mediator controls the transition from chromatin remodeling to transcription complex assembly.
The researchers' approach is to use purified proteins and biochemical methods to study various aspects of the mechanism of enhanceosome assembly, co-activator recruitment and chromatin remodeling. Their system is based on derivatives of the yeast transcriptional activator GAL4 (GAL4-VP16). GAL4 is a model system in which the activators and templates were constructed to experimentally manipulate various parameters important for activated transcription.
An important aspect of this work is applying the knowledge gained from its basic study toward the emerging field of molecular medicine. Carey and his colleagues have therefore begun employing the mechanistic information to develop highly active and specific vectors for gene therapy and cancer imaging. Their focus is on prostate cancer, which will strike more than 230,000 American men this year alone. Their work is done in collaboration with different members of the prostate oncology group at UCLA.
Selected Cancer-Related Publications:
Li B, Carey M, Workman JL. The role of chromatin during transcription. Cell. 2007; 128(4): 707-19.
Smallwood A, Esteve PO, Pradhan S, Carey M. Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev. 2007; 21(10): 1169-78.
Black JC, Choi JE, Lombardo SR, Carey M. A mechanism for coordinating chromatin modification and preinitiation complex assembly. Mol Cell. 2006; 23(6): 809-18.
Ilagan R, Pottratz J, Le K, Zhang L, Wong SG, Ayala R, Iyer M, Wu L, Gambhir SS, Carey M. Imaging mitogen-activated protein kinase function in xenograft models of prostate cancer. Cancer Res. 2006; 66(22): 10778-85.