Lack of responsiveness to TGF-beta1 in a thyroid carcinoma cell line with functional type I and type II TGF-beta receptors and Smad proteins, suggests a novel mechanism for TGF-beta insensitivity in carcinoma cells.
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine. In the present study we have investigated the expression of TGF-beta receptors (TbetaR's) and SMAD proteins in non-neoplastic and neoplastic thyroid follicle cells. We found expression of all TbetaR's (type I, II and III) and SMAD proteins analysed (Smad2, Smad3, Smad4, Smad6 and Smad7). Five out of six human anaplastic thyroid carcinoma cell lines were growth inhibited by addition of TGF-beta1, and therefore considered to be TGF-responsive. One cell line however, HTh 7, did not respond to TGF-beta1 with growth inhibition, induction of the extracellular matrix protein fibronectin or immediate early genes junB, Smad6 and Smad7 mRNA. Analysis of the TGF-beta intracellular signalling pathway in HTh 7 cells showed that receptors were capable of signalling, e.g. Smad2 phosphorylation and SMAD nuclear translocation. In summary, our data shows abundant expression of TGF-beta signalling components in thyroid follicle cells, and the escape from TGF-beta sensitivity in one anaplastic thyroid carcinoma despite an apparently functional TGF-beta/SMAD-signalling pathway, indicating a novel mechanism for TGF-beta insensitivity.
Heldin
N E
NE
Department of Genetics and Pathology, University Hospital, Uppsala, Sweden. nils-erik.heldin@patologi.uu.se
Bergström
D
D
Hermansson
A
A
Bergenstråhle
A
A
Nakao
A
A
Westermark
B
B
ten Dijke
P
P
D030201:Activin Receptors, Type I; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D016259:Genes, myc; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D051905:Smad6 Protein; D051906:Smad7 Protein; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C497802:SMAD6 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D051905:Smad6 Protein; D051906:Smad7 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