Lene Holland, Ph.D.

Associate Professor HollandL@missouri.edu

Research Interests

Steroid hormones control the activity of target cells by modulating expression of specific genes. The hormones bind to receptor proteins that interact with DNA and, together with other DNA-binding proteins, stimulate or repress transcription of nearby genes. The steroid hormone receptors belong to a large family of proteins called nuclear receptors, which regulate a very wide variety of physiological processes throughout the body. The focus of research in my laboratory is to analyze the molecular mechanisms underlying transcriptional regulation by the nuclear receptors. We use the liver of the frog Xenopus laevis as a model system. In the liver, synthesis of the three subunits of the critical blood-coagulation protein, fibrinogen, is controlled by adrenal steroids of the glucocorticoid class. Using several parallel approaches, including primary cell culture, introduction of purified genes into isolated liver cells, and analysis of DNA:protein binding interactions, the laboratory has identified the essential DNA sequences and protein factors required for hormone-induced expression of the fibrinogen genes. We are particularly interested in a DNA-binding protein, called Xenopus Glucocorticoid Receptor Accessory Factor (XGRAF) that is required, together with the hormone receptor, to simulate expression of the gamma fibrinogen subunit gene in response to glucocorticoids. The position of the XGRAF binding site in the gene upstream region is interesting, because it is directly adjacent to a sequence that binds a monomer of the glucocorticoid receptor (GR). We have shown that XGRAF and GR form a novel heterodimeric transcriptional regulatory complex. The long-term goal is to identify and purify XGRAF and to elucidate its unique role in glucocorticoid regulation of gene transcription. This knowledge will contribute to understanding, in general, the function of multiple protein factors acting on individual genes to elicit the appropriate overall physiological response to a steroid hormone signal.

Professional Background

• Received B.A. in biochemistry, University of California, Berkeley
• Received Ph.D. in biochemistry and biophysics, University of California, San Francisco
• Completed postdoctoral studies at Brandeis University
• Joined Department in 1990
• Sources of research funding: National Institutes of Health, American Heart Association
• Member of Molecular Endocrinology editorial board
• Member of Molecular and Cellular Endocrinology Study Section, National Institutes of Health

Selected Publications

• Woodward, R.N., Li, M., and Holland, L.J. Novel accessory factor-binding site required for glucocorticoid regulation of the gamma-fibrinogen subunit gene from Xenopus laevis. Molecular Endocrinology 11:563-576 (1997).
• Li, M., Ye, X., Woodward, R.N., Zhu, C., Nichols, L.A., and Holland, L.J. Analysis of the DNA binding site for Xenopus glucocorticoid receptor accessory factor: Critical nucleotides for binding specificity in vitro and for amplification of steroid induced fibrinogen gene transcription. Journal of Biological Chemistry 273:9790 9796 (1998).
• Morin, B., Zhu, C., Woodcock, G.R., Li, M., Woodward, R.N., Nichols, L.A., and Holland, L.J. The binding site for Xenopus glucocorticoid receptor accessory factor and a single adjacent half GRE form an independent glucocorticoid response unit. Biochemistry 39:12234 12242 (2000).
• Morin, B., Woodcock, G.R., Nichols, L.A., and Holland, L.J. Heterodimerization between the glucocorticoid receptor and the unrelated DNA binding protein, Xenopus glucocorticoid receptor accessory factor. Molecular Endocrinology 15:458-466 (2001).

Methodology/Techniques