Dominant negative mutants of transforming growth factor-beta 1 inhibit the secretion of different transforming growth factor-beta isoforms.
Transforming growth factor-beta (TGF-beta) is a secreted polypeptide factor that is thought to play a major role in the regulation of proliferation of many cell types and various differentiation processes. Several related isoforms have been structurally characterized, three of which, TGF-beta 1, -beta 2, and -beta 3, have been detected in mammalian cells and tissues. Each TGF-beta form is a homodimer of a 112-amino-acid polypeptide which is encoded as a larger polypeptide precursor. We have introduced several mutations in the TGF-beta 1 precursor domain, resulting in an inhibition of TGF-beta 1 secretion. Coexpression of these mutants with wild-type TGF-beta 1, -beta 2, and -beta 3 results in a competitive and specific inhibition of the secretion of different TFG-beta forms, indicating that these mutated versions act as dominant negative mutants for TGF-beta secretion. Overexpression of dominant negative mutants can thus be used to abolish endogenous secretion of TGF-beta and structurally related family members, both in vitro and in vivo, and to probe in this way the physiological functions of the members of the TGF-beta superfamily.
Lopez
A R
AR
Department of Developmental Biology, Genentech Inc., South San Francisco, California 94080.
Cook
J
J
Deininger
P L
PL
Derynck
R
R
D001693:Biological Transport, Active; D002460:Cell Line; D015870:Gene Expression; D005799:Genes, Dominant; D014644:Genetic Variation; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D021382:Protein Sorting Signals / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D011498:Protein Precursors; D021382:Protein Sorting Signals; D016212:Transforming Growth Factor beta