Professor of Biochemistry and Molecular Biology
3206 Molecular Biology Building
B.S. in Biochemistry, 1969, Cornell University; Ph.D. in Biochemistry, 1973, Cornell University; Postdoctoral Fellow, 1973-1975, The Salk Institute, San Diego, California
Research Interests: regulation of gene expression by growth factors in animal cells; tissue-specific regulation of gene expression; imaging gene expression; interaction between mother and fetus during reproduction
Growth factors regulate proliferation and other cellular activities that result in coordinated growth and differentiation of animal tissues. The expression and action of growth factors in vivo is associated with normal and abnormal proliferation in the adult animal. For example, growth factors participate in normal processes such as fetal development, wound-healing, and hematopoiesis and in abnormal processes such as cancer and atherosclerosis.
To achieve their effects, growth factors regulate gene expression and thus the production of new proteins. Dr. Nilsen-Hamilton has discovered that some of the most dramatic increases in gene expression brought about by growth factors are in genes encoding proteins that are secreted by cells. Some of these secreted proteins alter the environment surrounding the cells and others are communicating molecules which deliver a message to other cells.
Dr. Nilsen-Hamilton has discovered several secreted proteins and their genes that are regulated by growth factors. One family of proteins (MRP/PLFs), originally called "mitogen-regulated proteins" (MRPs) and later called proliferin (PLF) are related in sequence to the hormone, prolactin. They are made by the fetal placenta and by other fetal and adult cell types. The group has shown that these proteins stimulate the growth of uterine cells and therefore they may carry a message from the fetus to the mother by stimulating uterine growth. The research team is exploring the means by which the MRP gene is regulated by growth factors, how this protein delivers its message (e.g. the nature of its receptor), and the signals generated by the receptor in response to hormone binding.
More recently, the group has found that the mrp/plf genes are expressed during wound healing and also in some fetal tissues. Mrp3 is the main mrp/plf that is expressed in the wound. The mrp3 gene is also the only gene that is regulated by fibroblast growth factor, a protein that is produced in wounded tissues. The Nilsen-Hamilton group have discovered a very specific promoter element that they call the FGF-regulatory element (FRE) that specifically responds to FGF stimulus by turning on gene expression. Another gene (mrp4) is specifically expressed in the tail and ears of the mouse. Because the mrp4 promoter is 98% identical with the mrp3 promoter and yet they are expressed in different tissues under different controls, this provides an excellent system for comparative analysis of promoter elements and for the rapid identification of elements that are specifically involved in the tissue and cell-specific regulation of these genes.
Uterocalin is another secreted protein that is regulated by growth factors. It is an acute phase protein, produced by the liver in response to stress such as occurs with infections. Uterocalin is also produced by the uterus around birth. The protein is a lipocalin and may be involved in the protection of the uterus from infections by microbes during the time it is exposed to the environment in the birth process. It is also expressed at very high levels in the mammary gland and may be involved in protecting the gland from bacterial infection. The cDNA for uterocalin has been cloned and expressed and the group is now underway in studies to understand the protein's function and to understand how the gene is regulated.
To understand how growth-factor-induced genes are regulated and to identify the physiological functions of the protein products, Dr. Nilsen-Hamilton and her group are using biochemical, molecular, cellular, and developmental approaches, which include purifying the proteins, cloning the genes, determining their sequences, identifying the relevant regulatory elements, and identifying new transcriptional regulators. They are using cell cultures to express the proteins and also as "reporter" systems to study the activity of the regulatory elements of each gene. Studies of the regulation of gene activity also involve functional in vitro assays such as the electrophoretic mobility shift assay for transcription factors and in vivo studies of the levels of expression of the gene under different physiological conditions.
These studies are leading to a better understanding the role of growth factors and the genes they regulate in fetal development and in events of tissue remodeling such as wound healing. They are providing new information about the molecular mechanisms by which genes are regulated by growth factors and how the fetus and the mother communicate during pregnancy. There is also a promise with uterocalin that we will gain a new understanding of how the genes are regulated that are involved in natural mammalian defenses against microbial infection.
As well as their research activities, Dr. Nilsen-Hamilton and her group organize a series of symposia on growth factors and signal transduction. These annual symposia are broadly based and cover biochemical, molecular, cellular, and developmental biology topics. They provide the group and other ISU scientists with invaluable opportunities to interact with top U.S. and foreign scientists who are interested in growth factors, development, and signal transduction. Dr. Nilsen-Hamiltom also participates in a USDA Fellowship program.
Selected Publications:
Fassett JT, Hamilton RT, and Nilsen-Hamilton M (2000) Mrp4, A New Mitogen-Regulated Protein/Proliferin Gene; Unique in this Gene Family for its Expression in the Adult Mouse Tail and Ear. Endocrinology, 141:1863-1871
Levine HA, Sleeman BD, and Nilsen-Hamilton M (2000) A Mathematical Model for the Roles of Pericytes and Macrophages in the Onset of Angiogenesis: I. The Role of Protease Inhibitors in Preventing Angiogenesis. J Mathematical Biology, In press
Levine HA, Sleeman BD, and Nilsen-Hamilton M (2000) Mathematical Modeling of the Onset of Capillary Formation Initiating Angiogenesis. Mathematical Biosciences, In press
Bendickson L and Nilsen-Hamilton M (2000) "Western Blotting" In Basic Methods in Antibody Production and Characterization (GC Howard and DR Bethell, editors) CRC Press
Fang Y, Lepont P, Fassett J, Ford SP, Mubaidin A, Hamilton RT, and Nilsen-Hamilton M (1999) Signaling Between the Placenta and the Uterus Involving the Mitogen-Regulated Protein/Proliferins. Endocrinology, 140:5239-5274
Mohideen M-A PC, Hruska-Hageman A, and Nilsen-Hamilton M (1999) A Unique bFGF-Responsive Transcriptional Element. Gene, 237:81-90
Allen MP and Nilsen-Hamilton M (1998) "Granzymes D, E, F, and G are regulated through pregnancy and by interleukins 2 and 15 in granulated metrial gland cells." J. Immunology, 161:2772-2779
Molecular Reproduction and Development, (1997) Conference Proceedings on "Colony Stimulating Factor in Development and Disease." (M. Nilsen-Hamilton and J. Schmidt, eds.) Vol. 46, Wiley-Liss, Bethesda, MD
Liu Q, Ryon J and NilsenHamilton M (1997) "Uterocalin, a mouse acute phase protein expressed in the uterus around birth." Molecular Reproduction and Development 46:507-514
Liu Q and Nilsen-Hamilton M (1995) "Identification of a new acute phase protein." J. Biol. Chem. 270:22565-22570
Chuang T-H, Hamilton RT and Nilsen-Hamilton M (1995) "Cloning of mink plasminogen activator inhibitor type 1 messenger RNA; an mRNA with a short half life." Gene 162, 303-308
Nelson JT, Rosenzweig N and Nilsen-Hamilton M (1995) "Characterization of the mitogen-regulated protein (MRP; Proliferin) receptor." Endocrinology 136, 283-288
Nilsen-Hamilton M (Ed) (1994) Modern Cell Biology,"Growth Factors and Signal Transduction in Development." Wiley-Liss, Bethesda, MD
Thalacker FW and Nilsen-Hamilton M (1992) "Opposite and independent actions of cAMP and TGF-ß in the regulation of type 1 plasminogen activator inhibitor expression." Biochem J. 287, 855-862
Hamilton RT, Delgado MA, Shim J-K, Denhard DT and Nilsen-Hamilton M (1991) "Expression of cathepsin L and c-rasHa oncogene during mouse placental development." Molecular Reproduction and Development 30, 285-292
Nilsen-Hamilton M, Jang Y-J, Delgado M, Shim J-K, Bruns K,
Chiang C-P, Fang Y, Parfett CLJ, Denhard DT and Hamilton RT
(1991) "Regulation of the expression of mitogen-regulated
protein (MRP; Proliferin) and cathepsin L in cultured cells and
in the murine placenta." Mol Cell Endo 77,
115-122
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