SCIENCE TIP SHEET September 1998
Contacts: Karen Young Kreeger or Franklin Hoke
(215) 662-2560
[email protected]
[email protected]
Philadelphia, Pa. -- Below are three story ideas based on ongoing research at the University of Pennsylvania Medical Center.
A Role for Prolactin in Breast Cancer: Under normal circumstances, the hormone prolactin is responsible for stimulating breast tissue growth and differentiation at several times during a woman's life -- during puberty, pregnancy, and lactation. Unfortunately, it can also stimulate the growth of breast cancers that may arise, according to Charles V. Clevenger, MD, PhD, an assistant professor of pathology and laboratory medicine. Additionally, recent results from Clevenger's laboratory suggest that prolactin's role in the disease may be much greater than previously thought. Scientists examining breast cancer tissues in the past estimated that between 20 and 60 percent of these cancers expressed the receptor for prolactin, meaning that they would be responsive to the stimulatory effects of the hormone. Using improved techniques, Clevenger's team has found that a much higher proportion of breast cancers -- more than 95 percent -- express the prolactin receptor. Also, prolactin is ! known to be secreted by the pituitary gland, and for many years it was assumed that this gland was the only source for the hormone. Clevenger's laboratory, however, has shown that breast tissue itself produces prolactin in significant quantities. "Not only do most mammary tissues make their own prolactin, but so do most breast cancers," Clevenger notes. Coupled with the newly demonstrated prevalence of the prolactin receptor, the findings suggest that prolactin is likely serving to stimulate the growth of these cancers in most cases. While the news may not appear to be positive, it does present an opportunity for the development of important new therapies. "If we can find a way to block prolactin from binding to its receptor, we may be able to induce regression in breast tumors," Clevenger says. "They might stop growing, and they might even die." And, unlike some other hormone-based therapies for breast cancer, such as the new drug herceptin, which is useful in only a minority of patients, treatments focusing on prolactin and its receptor would benefit the majority of women with breast cancers.
Proteins Deep Inside the Nucleus Hold Clues for Two Diseases: For the past decade the lab of Gideon Dreyfuss, PhD, the Isaac Norris professor of biochemistry and biophysics at Penn and a Howard Hughes Medical Institute investigator, has centered on the mechanisms of how the genetic code is translated, via messenger RNA (mRNA), to correctly construct proteins that orchestrate the human body. This very basic work has turned out to have profound clinical implications for understanding two genetic conditions -- fragile X syndrome, the most common cause of hereditary mental retardation; and spinal muscular atrophy (SMA), the leading genetic cause of infant death. Specifically, the Penn group has focused on a group of 20 RNA-binding proteins called hnRNPs, which are important in the formation of mRNA. "In terms of clinical relevance, perhaps the most important area that we now work on is spinal muscular atrophy," notes Dreyfuss. Reduced levels or mutations in a protein called SMN le! ads to this disease, which is characterized by degeneration of motor nerve cells in the spinal cord. SMN (survival of motor neurons) interacts with one type of hnRNP. Essentially, these two proteins must work in concert so that motor neurons can function properly. When SMN is mutated the capacity of the cell to produce mRNA is impaired, leading to motor neuron death. Most recently, Dreyfuss and his team found that the SMN protein was concentrated in newly found cell-nuclei structures they dubbed Gemini coiled bodies, or gems, because they resembled companion structures in other cells. Their function still remains a mystery, but is somehow related to the genesis of mRNA. Interestingly, in the most severe type of spinal muscle atrophy, gems are almost completely absent. In both SMA and fragile X syndrome, Dreyfuss hopes that understanding the role of nuclear proteins and their interactions with other proteins will lead to therapies and a better understanding of the pathogenesis ! of each condition.
Tightly Controlled Protein Destruction Drives the Cell Cycle: Ubiquitin -- as the name suggests -- is found in cells throughout the body. In fact, this 76-amino-acid-long protein appears in nearly identical form in many other species, even some quite distant from humans on the phylogenic tree. Yeast ubiquitin, for example, differs from the human protein by only three of its amino-acid building blocks. What, then, makes ubiquitin so vital that it has been so strongly conserved during evolution? Research from the laboratory of Sandra L. Holloway, PhD, an assistant professor of genetics at Penn and assistant investigator with the Howard Hughes Medical Institute, is beginning to answer that question. Holloway's studies have shown that ubiquitin plays a crucial role in precisely coordinating the transition between two steps in mitosis, a step in the cycle of cell division that underlies all growth, renewal, and repair. After the cell has duplicated the DNA in its chromosomes in the metaphase step of mitosis, but before the chromosomes have separated in the anaphase step, a group of 13 proteins known as the anaphase-promoting complex, or APC, identifies and tags pivotal metaphase proteins with ubiquitin. Then, in a process referred to as ubiquitin-mediated proteolysis, a large tubular enzyme called a proteosome recognizes the protein-ubiquitin pairing and destroys the protein while releasing the ubiquitin to be used again. The destruction of the metaphase proteins frees the cell to continue to the anaphase step in the cell cycle. Currently, experiments ! in Holloway's laboratory are aimed at understanding precisely which APC proteins see and bind to specific proteins to facilitate the metaphase-anaphase transition. Her team recently discovered that an APC component called CDC23 binds to cyclin, a protein known to be essential in earlier steps of mitosis, leading to its destruction. According to Holloway, disruptions in the ubiquitin system have been linked to a number of human diseases, including colorectal and other cancers, Parkinson's disease, Alzheimer's disease, cystic fibrosis, Down's syndrome, and less common disorders such as Liddle's syndrome and Angelman syndrome. A better understanding of ubiquitin-mediated proteolysis, therefore, could form the basis for the development of new drugs to treat these and other diseases.
The University of Pennsylvania Medical Center's sponsored research ranks third in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation. In federal fiscal year 1997, the medical center received $175 million. News releases from the medical center are available to reporters by direct E-mail, fax, or U.S. mail, upon request. They are also posted to the center's website (http://www.med.upenn.edu); and Newswise (http://www.newswise.com).
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