Post by admin on Sept 17, 2005 16:54:47 GMT -5
Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2003
National Cancer Institute (NCI)
Overview of Rare Diseases Research Activities
A Novel Transcriptional Target in Desmoplastic Small Round-Cell Tumor (DSRCT) is Implicated in Tumor Invasiveness and Contributes to the Malignant Properties of DSRCT
A wide variety of human malignancies is associated with aberrant transcription factors—important components of the cell's machinery that regulate the expression of proteins. Desmoplastic small round-cell tumor (DSRCT) is a highly aggressive primitive tumor arising from the surface of the abdominal peritoneum. Virtually all cases are defined by a chimeric transcription factor that results from fusion of the N-terminal domain of the Ewing's sarcoma gene (EWS) to the transcription factor domain of the Wilms' tumor suppressor (WT1). In each case, the chimeric transcription factor has functionally novel and distinct properties. Multiple lines of evidence demonstrate that the biology of these chimeric transcription factors is central to the development and maintenance of these tumors.
In the case of the DSRCT, the WT1 transcript is alternatively spliced to yield a number of isoforms, the most abundant of which has a 3 amino acid insertion that interrupts the last WT1 zinc finger. The EWS-WT1 fusion protein fails to bind to the known WT1 consensus binding site and does not transactivate known targets of WT1. Using cDNA subtractive hybridization, an NCI-supported research team has identified a novel target gene for EWS-WT1, called LRRC15. They have demonstrated direct binding of EWS-WT1 to a specific DNA sequence upstream of LRRC15 and potent transcriptional activation.
LRRC15 appears to be a protein whose normal role may be linked to placental invasion and which appears to be "misappropriated" by specific types of human cancer. LRRC15 protein is expressed exclusively at the leading edge of migrating cells. A role for LRRC15 in cellular invasion is suggested by its striking expression solely within the cells of the placenta that invade the uterus during implantation. This is supported by the expression of LRRC15 in primary DSRCT tumor specimens and by data demonstrating reduced invasion of breast cancer cells after specific suppression of LRRC15 expression. Approaches designed to inhibit LRRC15 function may have therapeutic potential in this refractory human cancer.
A wide variety of human malignancies is associated with aberrant transcription factors—important components of the cell's machinery that regulate the expression of proteins. Desmoplastic small round-cell tumor (DSRCT) is a highly aggressive primitive tumor arising from the surface of the abdominal peritoneum. Virtually all cases are defined by a chimeric transcription factor that results from fusion of the N-terminal domain of the Ewing's sarcoma gene (EWS) to the transcription factor domain of the Wilms' tumor suppressor (WT1). In each case, the chimeric transcription factor has functionally novel and distinct properties. Multiple lines of evidence demonstrate that the biology of these chimeric transcription factors is central to the development and maintenance of these tumors.
In the case of the DSRCT, the WT1 transcript is alternatively spliced to yield a number of isoforms, the most abundant of which has a 3 amino acid insertion that interrupts the last WT1 zinc finger. The EWS-WT1 fusion protein fails to bind to the known WT1 consensus binding site and does not transactivate known targets of WT1. Using cDNA subtractive hybridization, an NCI-supported research team has identified a novel target gene for EWS-WT1, called LRRC15. They have demonstrated direct binding of EWS-WT1 to a specific DNA sequence upstream of LRRC15 and potent transcriptional activation.
LRRC15 appears to be a protein whose normal role may be linked to placental invasion and which appears to be "misappropriated" by specific types of human cancer. LRRC15 protein is expressed exclusively at the leading edge of migrating cells. A role for LRRC15 in cellular invasion is suggested by its striking expression solely within the cells of the placenta that invade the uterus during implantation. This is supported by the expression of LRRC15 in primary DSRCT tumor specimens and by data demonstrating reduced invasion of breast cancer cells after specific suppression of LRRC15 expression. Approaches designed to inhibit LRRC15 function may have therapeutic potential in this refractory human cancer.