DESCRIPTION (provided by applicant): Transforming Growth Factor Beta (TGF-beta) is one of the most potent naturally occurring inhibitors of normal cell growth.
TGF-beta exerts its action by binding to a type I (TbR-I) and a type II
(TbR-II) transmembrane receptor located on the cell membrane. Downstream
signaling is mediated by TbR-I once the ligand has bound both receptors. Three
proteins, Smad2, Smad3 and Smad4/DPC4 have been found to be essential
downstream components of the TGF-beta signaling pathway in mammalian cells. My
work has led to the discovery of the first mutations of the type I TGF-beta
receptor, a 9-bp deletion and 3-bp insertion coined TbR-I(6A) and TbR-I(10A),
respectively. My most recent data indicate that the frequency of TbR-I(6A)
heterozygotes and homozygotes is significantly higher in patients with cancer
than in healthy blood donors of comparable ethnic status. However, TbR-I(6A)
heterozygotes and especially TbR-I(6A) homozygotes carriers appear to be at
greater risk of developing cancer. This observation is particularly striking in
colorectal cancer. Indeed, 19 percent of the patients studied so far exhibited
TbR-I(6A) homozygosity or heterozigosity. Stable transfection of mink lung
epitheliall cell lines devoid of TbR-I with either TbR-I or TbR-I(6A) shows
that TbR-l(6A) transduces less effectively TGF-beta mediated growth inhibition
than TbR-I. Thus, TbR-I(6A) acts as a common TbR-I polymorphic allele
compatible with normal human development. The higher than expected number of
TbR-I(6A) heterozygotes and especially TbR-I(6A) homozygotes among cancer
patients suggests that TbR-I(6A) is a candidate tumor susceptibility allele.
This application's objectives are to test further the hypothesis that TbR-I(6A)
and/or TbRI(10A) may be associated with the development of malignancy. It aims
at determining: 1) The prevalence of TbR-I(6A) heterozygosity and homozygosity
among the various ethnic groups of a healthy population, 2) Which human cancers
may or may not be associated with the homozygous TbR-I(6A) and heterozygous
TbR-I(6A) genotype, 3) Whether TbR-I(6A) is associated with certain forms of
hereditary colon cancer, 4) The turnover as well as the proportion of cell
surface and intracellular TbR-I and TbR-I(6A) receptors. Should TbR-I(6A) turn
out to be a tumor susceptibility allele, the plan described in this application
will serve as a basis for planning future clinical project grant applications.
TbR-I(6A) homozygotes and TbR-I(6A) heterozygous carriers may have a higher
risk to develop certain forms of cancer and may benefit from early screening.
The clinical course of TbR-I(6A) carriers will need to be investigated as TbR-I
status may have prognostic significance. Hence, this project has a high
potential for translation of research to clinical applications.
If you are accessing this page during weekend or evening hours, the database may currently be offline for maintenance and should operational within a few hours. Otherwise, we have been notified of this error and will be addressing it immediately.
Please contact us
if this error persists.
We apologize for the inconvenience.
- The DCCPS Team.