Project: Research project

Project Details


DESCRIPTION (Applicant's abstract reproduced verbatim): Neuroblastoma (Nb) is
the most common solid tumor in children. Despite intensive treatment regimens,
however, Nb has a relatively poor prognosis in advanced stages and accounts for
15 percent of all childhood deaths due to cancer. Stage 4S disease is a special
variant form of Nb which occurs in infants under the age of 12 months and, even
despite a large tumor load and distant metastases, these tumors will often
regress spontaneously. Identifying the genes which allow this rapid expansion
and metastasis of neuroblasts will be invaluable in understanding the early
stage of Nb tumorigenesis. Constitutional chromosome translocations have been
instrumental in the identification of genes responsible for a wide variety of
human genetic diseases, where it has been shown that the function of critical
genes is affected in some way by the breakpoints. We have recently cloned the
genes interrupted by a constitutional 1;10 chromosome translocation from a
patient who developed stage 4S neuroblastoma. The 1p22 chromosome breakpoint
occurs within the NB4S gene. This gene has two identifiable motifs: a TBC1
domain and a coiled-coil domain. Both of these motifs are indicative of
protein-protein interactions. The gene on chromosome 10, TRNG10, is a member of
an emerging class of genes which are transcribed but not translated. This gene
is overexpressed in cancer cells compared with normal cells. As a result of the
translocation the TBC1 domain of NB4S is truncated by in-frame fusion to
TRNG10. Mutation analysis of NB4S does not indicate that it functions as a
tumor suppressor gene. Transfection studies, on the other hand, indicate that a
truncated form of NB4S is a dominantly transforming oncogene. To establish the
function of the novel chimeric gene we will undertake a series of in vitro
studies to characterize the dominant transforming activity, as well as the
spatial and temporal expression pattern. We will also use immunoprecipitation
and yeast-two hybrid analysis to define interacting genes that may be important
for function. In an attempt to establish a mouse model for 4S neuroblastoma, we
will express the chimeric gene in transgenic mice. As a result of an improved
understanding of the genetic events that give rise to Nb, it may eventually be
possible to design novel therapeutic approaches directed against the gene and
its product, as well as to assess their value in the pre-symptomatic
identification of at-risk individuals.
StatusNot started


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