Signal protein shows promise for blocking tumor promoters in skin cells

Implications for targeted gene therapy of selected cancers



Mouse skin from transgenic mice shows prominent expression of a protein called Fyn (brown color, left). Levels of Fyn drop dramatically in Fyn/Srcasm mice, which has increased levels of the...
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(Philadelphia, PA) -- A protein with the ironic name "Srcasm" can counteract the effects of tumor-promoting molecules in skin cells, according to new research by investigators at the University of Pennsylvania School of Medicine. Using animal models, the researchers discovered that Srcasm acts like a brake in epithelial cells, preventing uncontrolled cell growth caused by a family of proteins called Src kinases. This finding, published online in the Journal of Biological Chemistry, suggests a target for future gene therapy to treat skin, head, neck, colon, and breast cancers.

Investigators have known for decades that Src kinase proteins can promote tumor formation. Src kinase activity is elevated in most skin cancers and in common carcinomas, including those of the breast and colon. At the same time, levels of the signaling molecule Srcasm are typically low in tumor cells, notes senior author John Seykora, MD, PhD, Assistant Professor of Dermatology. The current findings show that Srcasm can reduce the amount of Src kinases in cells; they have also shown that increased activity of these kinases is associated with cancerous skin lesions.

Src kinase proteins act like messengers, sending signals that control cellular growth. Found just inside the cell membrane, they conduct signals from cell surface receptors to the proteins that promote growth. Src kinases can be activated during cell division or through mutation. If these proteins are too active, they promote rapid cell growth that can spin out of control. In skin cells, Src kinases and Srcasm are involved in signaling pathways that control cell growth and differentiation.

See Saw Action
The researchers decided to test whether Srcasm could counteract the errant effects of Src kinases. They developed strains of mice with high levels of Srcasm, which had normal skin, and other strains that over-expressed the Src-kinase called Fyn, which resulted in uncontrolled cell growth with thick, scaly, hairless plaques on the skin. These plaques, or lesions, resembled precursors of cancer. Breeding experiments with the mice indicated that high Srcasm levels counteracted the effects of Fyn.

The findings reveal that levels of Fyn and Srcasm work in a kind of see-saw when Srcasm production is low, dangerous amounts of Fyn can build up in cells. But when Srcasm production is increased, Fyn levels go down. "The binding of Srcasm to Fyn regulates Fyn's persistence in the cell," says Seykora. "If Srcasm is low, Fyn persists longer and sends more growth-promoting signals."

Reversing Tumors
Eventually, Srcasm might play a role in targeted gene therapies for cancers that are triggered by activated Src kinases. Such a therapy would likely use an adenovirus to carry a gene that codes for Srcasm into skin cells to increase Srcasm production, as used in some other gene therapy treatments. Initially, clinicians may try this method on oral cavity and skin cancers.

Next, the Penn researchers will determine whether Srcasm can actually reverse tumor formation in skin. Seykora's team has already prepared an adenovirus and mice with the tumor-forming Src kinases expressed in their skin. Within six months, the group expects to know whether Srcasm can decrease squamous cell carcinoma formation in skin, mentions Seykora.

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This research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Other co-authors in addition to Seykora are Weijie Li, Christine Marshall, Lijuan Mei, and Joel Gelfand, all from Penn.

PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors (Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center); a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.


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