The loss of function of a gene called FOXO1a plays an important role in the development of the most common cancer of soft tissues in children, and restoring the function of that gene in cancer cells suppresses that cancer, according to investigators at St. Jude Children's Research Hospital. The cancer, called alveolar rhabdomyosarcoma (ARMS), arises from immature skeletal muscle cells that remain partially differentiated (do not acquire all the characteristics of a mature muscle cell).

The St. Jude team found that the expression of FOXO1a is suppressed in ARMS and that the gene potently suppresses tumor activity when re-introduced into ARMS tumor cells in the laboratory. Therefore, the investigators theorize that the observed loss of FOXO1a activity is a pivotal step in the ARMS development. The FOXO1a gene produces the protein FOXO1a. Gene expression refers to the production of the protein coded for by a particular gene. A report on these findings appears in the September 12 issue of Journal of Cell Biology.

FOXO1a kills ARMS cells by activating the gene that produces a protein called caspase-3. Caspase-3 is a key player in the signaling pathway that triggers programmed cell death (apoptosis). Although caspase-3 triggers apoptosis in abnormal cells, normal myoblasts (immature muscle cells) also depend on caspase-3 activity in order to differentiate into mature muscle cells.

"Our study shows that suppression of FOXO1a is necessary for ARMS cells to survive and avoid caspase-3-mediated apoptosis, even in the more aggressive secondary tumors that are highly resistant to irradiation and chemotherapy, said Gerard Grosveld, Ph.D., chair of genetics and tumor cell biology at St. Jude. Grosveld is senior author of the paper. His team previously reported that FOXO1a (also called FKHR) is the master regulator that controls the differentiation of myoblasts into muscle cells (EMBO Journal 22:1147-1157; 2003).

The investigators also showed that the loss of
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Contact: Kelly Perry
kelly.perry@stjude.org
901-495-3306
St. Jude Children's Research Hospital
20-Sep-2005

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