Somatostatin is expressed in FRTL-5 thyroid cells and prevents thyrotropin-mediated down-regulation of the cyclin-dependent kinase inhibitor p27kip1.
Using RT and amplification, we have detected specific RNA transcripts encoding somatostatin in FRTL-5 thyroid cells. This observation indicates that within the thyroid context, expression of somatostatin is not restricted to the parafollicular C cells. Transfection of FRTL-5 cells with constructs containing either the complete somatostatin gene promoter or deletions carrying the cAMP response element-binding site allowed us to demonstrate that transcription of the somatostatin gene is hormonally regulated by TSH. Blockage of somatostatin by specific antibodies resulted in an increased capacity of TSH-induced FRTL-5 cell-conditioned medium to promote cell proliferation, demonstrating that under physiological conditions, somatostatin exerts a cytostatic effect on FRTL-5 cells growth. Somatostatin treatment of FRTL-5 cells resulted in a growth retardation, caused by a dose-response delay in the G1 phase of the cell cycle. This effect appears to be mediated by the cyclin-dependent kinase inhibitor p27kip1, which is clearly down-regulated in FRTL-5 cells treated with TSH and whose expression is reestablished by somatostatin in a dose-dependent manner. Participation of somatostatin in the control of FRTL-5 cell proliferation is in agreement with the detection of specific somatostatin receptor type 2. Flow cytometric assays reveal that FRTL-5 cells transformed with the K-ras oncogene are still sensitive to somatostatin treatment, whereas fully neoplastic FRT cells no longer respond to this peptide. Taking together, the results demonstrate the participation of an autocrine loop in the control of thyroid cell proliferation, and the possibility that this mechanism could be altered in the process of thyroid carcinogenesis.
Medina
D L
DL
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Velasco
J A
JA
Santisteban
P
P
D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division; D002469:Cell Separation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000096:biosynthesis* / Q000235:genetics; D013050:Spectrometry, Fluorescence; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D017481:Receptors, Somatostatin; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013004:Somatostatin; D013972:Thyrotropin; C093733:somatostatin receptor 2