Transforming growth factor beta 1 (TGF-beta 1) inhibits retinoblastoma gene expression but not pRB phosphorylation in TGF-beta 1-growth stimulated colon carcinoma cells.
The response of the retinoblastoma (RB) gene and its product (pRB) to transforming growth factor beta 1 (TGF-beta 1) was studied in three types of colon carcinoma cells derived from the same parental line. TGF-beta 1 was a growth inhibitor for two enterocytic-differentiated lines, a growth stimulator for two undifferentiated lines, and had no effect on two goblet cell-differentiated lines. TGF-beta 1 treatment for 3 days decreased RB gene expression and pRB level two- to threefold in each responsive line. When treated with TGF-beta 1 beginning in early G1, enterocytic cells were arrested in G1 and pRB remained under-phosphorylated and in low abundance. Neither goblet cell line exhibited these responses to TGF-beta 1 because they were shown to lack TGF-beta 1 type I and II receptors. Thus during colonocyte differentiation goblet cells lose responsiveness to TGF-beta 1 by down-regulating TGF-beta 1 receptors, while enterocytic cells retain and exhibit responsiveness to TGF-beta 1 through modulations of pRB. Both of the undifferentiated lines exhibited mixed responses to TGF-beta 1: a decrease in total amount of RB mRNA and pRB protein yet an increase in pRB phosphorylation consistent with increased cell cycling. Therefore, TGF-beta 1 controls RB function by two separable mechanisms, the regulation of pRB phosphorylation and the control of RB mRNA and protein level.
Yan
Z
Z
Memorial Sloan-Kettering Cancer Center, Department of Medicine, New York, New York 10021.
Hsu
S
S
Winawer
S
S
Friedman
E
E
D002277:Carcinoma / Q000503:physiopathology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000503:physiopathology*; D015870:Gene Expression / Q000187:drug effects; D016161:Genes, Retinoblastoma; D006801:Humans; D066298:In Vitro Techniques; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta