Evidence for c-myc in the signaling pathway for TGF-beta in well-differentiated human colon carcinoma cells.
Previously, we described a model culture system for comparing responsiveness of poorly differentiated and well-differentiated human colon carcinoma cells to exogenous growth factors. While polypeptide growth stimulators elicited an up-regulation of c-myc, as well as a mitogenic response in the well-differentiated cells, the poorly differentiated cells were insensitive to exogenous growth stimulators. We now show, by thymidine incorporation experiments and autoradiographic analysis, that transforming growth factor beta 1 (TGF-beta) abrogated the mitogenic responses to the growth factors epidermal growth factor + insulin + transferrin (IC50 = 0.8 ng/ml), as well as to nutrients (basal medium; IC50 = 0.2 ng/ml) in the well-differentiated cells. The poorly differentiated cells did not respond to TGF-beta. Moreover, TGF-beta (10 ng/ml) completely abrogated the growth factor-stimulated up-regulation of c-myc in the TGF-beta responsive, well-differentiated colon carcinoma cells. Addition of TGF-beta to the TGF-beta-responsive, well-differentiated cells, at a time after c-myc had been transiently up-regulated in response to growth stimulatory factors, resulted in a loss of responsiveness to TGF-beta. Addition of TGF-beta to these cells at increasing time periods after EIT stimulation also resulted in a loss of the TGF-beta-induced repression of c-myc. The results suggest an important role for c-myc in the mechanism of action of TGF-beta in well-differentiated human colon carcinoma cells.
Mulder
K M
KM
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.
Humphrey
L E
LE
Choi
H G
HG
Childress-Fields
K E
KE
Brattain
M G
MG
D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003110:Colonic Neoplasms; D003470:Culture Media; D005091:Exons; D016259:Genes, myc; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D003470:Culture Media; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm; D016212:Transforming Growth Factor beta