Jan. 16, 2005 Fox Chase Cancer Center researchers have made new discoveries that shed new light on the mystery of why human tissues, such as skin, age. The findings focus on the composition and assembly of key chromosomal protein complexes involved in shutting down reproduction of aging cells. The report by molecular and cell biologist Peter D. Adams, Ph.D. and his colleagues appears in the January 2005 issue of Developmental Cell.
"In the lab, aging cells are called senescent cells. Senescent cells are no longer able to divide but remain metabolically active," Adams explained. "Accumulation of senescent cells over time appears to contribute to changes in tissue form and function commonly associated with aging, like the skin changes that occur between childhood and old age."
Most normal human cells undergo a limited number of cell divisions but are eventually arrested, either through final differentiation or senescence. Differentiation is the process whereby a proliferating cell stops growing and develops into a cell with a specific function, such as a liver cell or a neuron. Senescence is an irreversible stage in a cell's life cycle and may underlie the human aging process and have an impact on diseases of aging, such as adult cancers.
"Most importantly, the failure of cells to stop growing through differentiation or senescence can lead to the uncontrolled growth of cancer," Adams emphasized. Both senescence and differentiation involve reorganization of chromatin structure --the complex of DNA, RNA and proteins, called histones, in the cell nucleus.
Previous research has shown that as cells reach senescence, a change in chromatin structure, called SAHF (senescence-associated heterochromatin foci), silences the genes that promote the cells' growth. Adams' discovery reveals the mechanism of SAHF formation. SAHF are domains of densely packed chromatin that repress activity of the genes that normally drive cell proliferation. Adams and coworkers have identified at least three proteins in the cell that contribute to formation of SAHF. These are called HIRA, ASF1a and PML. Of particular note, PML is named after acute promyelocytic leukemia, a cancer of white blood cells. Scientists have known for sometime that PML suppresses the formation of this cancer, but no one knew why.
Adams' work suggests the possibility that this cancer arises because PML is unable to do its job in forming SAHF. If so, then extrapolating from recent findings in other cancers, inactivation of PML, HIRA, ASF1a and formation of SAHF may also contribute to other human cancers.
Future work in Adams' lab will define the molecular details by which HIRA, ASF1a and PML make SAHF. Ultimately, this work might allow rationale design of therapeutics to treat cancer patients and even alleviate some aspects of human aging.
Adams' co-authors on the new paper include postdoctoral associates Rugang Zhang, Ph.D., and Xiaofen Ye, Ph.D., graduate student Maxim V. Poustovoitov of Russian State Medical University in Moscow, scientific technicians Hidelita A. Santos and Wei Chen, staff scientist Ilya G. Serebriiskii, Ph.D., structural and computational biologist Roland L. Dunbrack, Ph.D., and staff scientist Adrian A. Canutescu, M.D., all at Fox Chase; Sally M. Daganzo, Ph.D., Jan P. Erzberger, Ph.D., James M. Berger, Ph.D., and Paul D. Kaufman, Ph.D., of Lawrence Berkeley National Laboratory; and John R. Pehrson, Ph.D., of the University of Pennsylvania School of Veterinary Medicine.
Poustovoitov is working in Adams' laboratory as part of a novel partnership with the Russian medical and scientific institutions to provide training at Fox Chase for master's- and doctoral-level students. Begun in 1998 with Russian State Medical University, the partnership has expanded over the years to include more students and more affiliations with premier Russian research institutions. Students typically intern at Fox Chase for about 18 months, although several have chosen to continue their studies and pursue doctoral research in their host laboratory.
Adams is a Leukemia and Lymphoma Society Scholar. Grants from the Department of Defense, the National Institutes of Health and the American Federation for Aging Research also helped support the new work on senescent cells.
Fox Chase Cancer Center was founded in 1904 in Philadelphia as the nation's first cancer hospital. In 1974, Fox Chase became one of the first institutions designated as a National Cancer Institute Comprehensive Cancer Center. Fox Chase conducts basic, clinical, population and translational research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center's web site at http://www.fccc.edu or call 1-888-FOX CHASE.
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