(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.
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
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.
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.
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