Reconstitution of TGF-beta sensitivity in the VACO-411 human colon carcinoma line by somatic cell fusion with MCF-7.
We characterized the mechanism of transforming growth factor beta (TGF-beta) resistance in the VACO-411 human colon carcinoma line. VACO-411 is unique for several reasons, including having a novel mutator phenotype and wild-type p53. Like many colon tumors, VACO-411 is not growth inhibited by TGF-beta. However, VACO-411 represents a subset of colon tumors that are resistant to TGF-beta-mediated growth inhibition, despite the expression of functional TGF-beta receptors. VACO-411 expresses cell surface TGF-beta receptor types I and II, and the coding regions of these receptors are wild type. To further characterize the nature of the VACO-411 defect, we fused VACO-411 with the human breast carcinoma line MCF-7. MCF-7 is also resistant to TGF-beta-mediated growth inhibition. However, unlike VACO-411, MCF-7 lacks cell surface expression of TGF-beta receptor type II, but does contain an intact postreceptor signaling pathway, as shown by regeneration of TGF-beta sensitivity following wild-type TGF-beta receptor type II transfection. In contrast to parental VACO-411 and MCF-7, the morphologically distinct cell hybrids were growth inhibited by TGF-beta. Therefore, the TGF-beta defect in VACO-411 is a postreceptor, loss-of-function mutation which can be genetically complemented. The data suggest that the VACO-411 defect in TGF-beta signaling will be able to be further complemented by microcell-mediated chromosome transfer.
Traicoff
June L
JL
Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA. traicoju@csr.nih.gov
Periyasamy
Sumudra
S
Brattain
Michael G
MG
Grady
William
W
Casey
Graham
G
D001943:Breast Neoplasms / Q000378:metabolism*; D002459:Cell Fusion; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells; D008751:Methylene Blue / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D016212:Transforming Growth Factor beta; D008751:Methylene Blue