Three distinct isoforms of TGF-beta are expressed in mammals. Although each of these isoforms shows 65-85% homology to each other, the amino acid sequence of any particular isoform is conserved greater than 98% between mammalian, avian, and amphibian species. This strongly suggests that the mature peptides will have certain unique biological activities. Only TGF-beta's 1, and 2 have been purified from natural sources. So that we might be able to compare the activities of all three isoforms, we developed a system for expression of recombinant TGF-beta 3. Moreover, to begin to explore exactly which regions of the molecule are responsible for isoform-specific binding and activity, we have used this same expression system to express specific recombinant chimeric TGF-beta's in which regions of the amino acid sequence of TGF-beta's 1, 2, and 3 are substituted for each other in the mature peptide. Each of these recombinant TGF-beta's has been purified to homogeneity using a sequence of high pressure liquid chromatography steps. The availability of TGF-beta 3 has permitted us to raise antibodies against this peptide which can now be used to detect its presence in a variety of experimental systems. Moreover, selective effects of TGF-beta 3 have been identified in inhibition of the growth of hematopoietic cells, in migration of fetal fibroblasts, and in inhibiting the survival of certain neuronal cells. Using the chimeric TGF-beta constructs, we have been able to deduce that the middle third of the TGF-beta molecule is sufficient to confer isoform-specific biological activity. In a related aspect of this project, we are exploring the effects of the different TGF-beta isoforms on protection of cardiac myocytes from damage resulting from the action of growth factors such as interleukin-I and tumor necrosis factor-alpha.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CP005051-13
Application #
3853409
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Division of Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
United States
Zip Code