Transfection of the type I TGF-beta receptor restores TGF-beta responsiveness in pancreatic cancer.
Transforming growth factor-beta (TGF-beta) signaling is initiated following heterodimerization of the type II TGF-beta receptor (TbetaRII) with the type I TGF-beta receptor (TbetaRI). Both receptors are required for TGF-beta responsiveness. In the present study, we characterized the actions of TGF-beta1 in T3M4 human pancreatic cancer cells, which express low levels of TbetaRI and high levels of TbetaRII. Cells were transiently transfected with p3TP-Lux, a TGF-beta-responsive luciferase reporter gene construct. TGF-beta1 was without effect in parental T3M4 cells, but caused a time- and dose-dependent increase in luciferase activity in T3M4 cells co-transfected with a TbetaRI cDNA expression vector. Co-transfection of TbetaRI with a truncated Smad4 cDNA that is known to block TGF-beta-dependent signaling, abrogated the TbetaRI-induced increase in luciferase activity. Sequencing of the TbetaRI and the Smad4 genes in T3M4 cells did not reveal any mutations. These findings indicate that one mechanism for TGF-beta resistance in pancreatic cancer is due to a quantitative decrease in TbetaRI expression.
Wagner
M
M
Department of Medicine, University of California, Irvine 92697, USA.
Kleeff
J
J
Lopez
M E
ME
Bockman
I
I
Massaqué
J
J
Korc
M
M
D030201:Activin Receptors, Type I; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II