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Regulation of transforming growth factor beta 1 action by multiple transducing pathways: evidence for both G protein-dependent and -independent signaling.

Abstract：

:The effects of cholera toxin (CT) on transforming growth factor beta 1-stimulated protooncogene expression, [gamma-35S]GTP binding, GTPase activity and growth under anchorage-independent and -dependent conditions were studied in AKR-2B fibroblast cells. CT was shown to inhibit TGF beta 1-stimulated c-sis and c-myc mRNA expression. Actinomycin D decay and nuclear runon experiments demonstrated that this inhibition was not due to an increased decay of protooncogene message, but to a decreased transcriptional activation. These inhibitory effects were not secondary to changes in the ability of TGF beta 1 to bind to its receptor(s) since radioreceptor assays and affinity labeling studies demonstrated that CT had no effect on TGF beta 1 binding. ADP ribosylation of AKR-2B plasma membranes with [alpha-32P]NAD+ revealed a Mr 45,000 protein as the major CT substrate. The labeling of this Mr 45,000 protein in membranes could be inhibited by prior pretreatment of the cells with increasing concentrations of CT. Treatment of membranes with nanogram concentrations of CT abolished the increase in [gamma-35S]GTP binding following addition of TGF beta 1 as well as decreased basal binding. Similarly, CT pretreatment of membranes inhibited TGF beta 1-stimulated GTPase activity. Unexpectedly however, the stimulatory effects of TGF beta 1 on anchorage-independent growth in soft agar were unaffected by CT. Only pertussis toxin was able to inhibit TGF beta 1-induced colony formation in soft agar in a dose-dependent manner. Furthermore, differential effects of both CT and pertussis toxin were observed on TGF beta 1-stimulated monolayer growth; CT was inhibitory, whereas pertussis toxin was without effect. These results suggest that the diverse biological effects of TGF beta 1 are mediated through multiple intracellular pathways distinguishable by their toxin sensitivities.

journal_name

Cancer Res

journal_title

Cancer research

authors

Howe PH,Bascom CC,Cunningham MR,Leof EB

subject

Has Abstract

pub_date

1989-11-01 00:00:00

pages

6024-31

issue

eissn

0008-5472

issn

1538-7445

journal_volume

pub_type

杂志文章

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Regulation of transforming growth factor beta 1 action by multiple transducing pathways: evidence for both G protein-dependent and -independent signaling.