scholarly journals Tri-iodothyronine increases insulin-like growth factor binding protein-2 expression in cultured hepatocytes from hypothyroid rats

1999 ◽  
Vol 161 (3) ◽  
pp. 465-474 ◽  
Author(s):  
I Demori ◽  
C Bottazzi ◽  
E Fugassa
Keyword(s):  
Growth Factor ◽  
Thyroid Hormone ◽  
Binding Protein ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Cultured Hepatocytes ◽  
Factor Binding

Previous evidence suggests the existence of a thyroid hormone-IGF axis in the liver and changes in hepatic insulin-like growth factor binding protein (IGFBP) expression in rats with altered thyroid status have been previously reported. The aim of this study was to check if the higher IGFBP-2 mRNA levels observed in liver of hypothyroid rats could be due to a direct effect of thyroid hormone on the IGFBP-2 gene. In our experiments, cultured hepatocytes isolated from normal and hypothyroid adult rats were used. Northern blot analysis revealed barely detectable IGFBP-2 mRNA in normal rat hepatocytes, but easily detectable signal in hypothyroid rat cells. Therefore, the effect of tri-iodothyronine (T3) was investigated using cultured hepatocytes from hypothyroid rats as an in vitro model. The IGFBP-2 message was increased in a dose-dependent manner in hepatocytes cultured for 12-24 h in the presence of T3. A similar increase occurred in accumulation of IGFBP-2 in the culture medium, as measured by RIA. The effect of T3 on IGFBP-2 transcript levels appeared to consist of enhanced gene transcription and was independent of ongoing protein synthesis, but it was completely abolished by the incubation of hepatocytes with insulin. The latter result confirmed the dominant role of insulin in regulating IGFBP-2 expression by cultured hepatocytes. In vivo experiments confirmed an increase in hepatic IGFBP-2 mRNA and serum IGFBP-2 levels in hypothyroid rats and demonstrated, in addition, a significant increase in these measures in T3-treated rats. Taken together, our in vitro and in vivo results support a role for a thyroid hormone-IGF axis in the liver and suggest that other factors, such as insulin, interact in vivo with thryoid hormone in regulating hepatic IGFBP-2 expression.

Tri-iodothyronine increases insulin-like growth factor binding protein-4 expression in rat hepatocytes

1997 ◽  
Vol 154 (1) ◽  
pp. 155-165 ◽  
Author(s):  
I Demori ◽  
C Bottazzi ◽  
A Voci ◽  
G Gallo ◽  
J-G Scharf ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Mrna Level ◽  
Insulin Like Growth Factor ◽  
Cultured Hepatocytes ◽  
Adult Rats ◽  
Direct Role ◽  
Factor Binding ◽  
Rat Thyroid

Abstract Previous in vivo studies demonstrated significant variations in insulin-like growth factor binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-4 hepatic mRNAs and/or serum levels depending on the rat thyroid status. In this study we employed cultured hepatocytes from adult rats to demonstrate a possible direct regulation of these genes by tri-iodothyronine (T3). Northern blot analysis revealed that IGFBP-1 and -4 messages were clearly expressed, whereas IGFBP-2 signal was barely detectable. No significant effects on IGFBP-1 mRNA level or on peptide secretion were detected in T3-cultured hepatocytes. In contrast, significant increases in IGFBP-4 mRNA steady-state levels as well as in IGFBP-4 secretion were observed in hepatocytes cultured for 12–24 h in the presence of T3. The T3 effect on IGFBP-4 transcript levels appears to consist of enhanced gene transcription and is independent of ongoing protein synthesis. The T3-increased IGFBP-4 expression in cultured hepatocytes is consistent with our in vivo experiments demonstrating an increase in hepatic IGFBP-4 mRNA and serum IGFBP-4 levels in T3-treated rats. Furthermore, significant decreases in hepatic IGFBP-4 message and serum IGFBP-4 levels were observed in hypothyroid rats compared with euthyroid controls. Our data establish an important direct role for thyroid hormone in regulating IGFBP-4 expression and consequently IGF activity. Journal of Endocrinology (1997) 154, 155–165

Antagonistic effects of phorbol esters on insulin regulation of insulin-like growth factor-binding protein-1 (IGFBP-1) but not glucose-6-phosphatase gene expression

2001 ◽  
Vol 359 (3) ◽  
pp. 611-619 ◽  
Author(s):  
Satish PATEL ◽  
Pamela A. LOCHHEAD ◽  
Graham RENA ◽  
Calum SUTHERLAND
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Map Kinases ◽  
Phorbol Esters ◽  
Binding Protein ◽  
Gene Promoter ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Factor Binding

Glucose-6-phosphatase (G6Pase) and insulin-like growth factor-binding protein-1 (IGFBP-1) genes contain a homologous promoter sequence that is required for gene repression by insulin. Interestingly, this element interacts with members of the forkhead family of transcription factors [e.g. HNF3 (hepatic nuclear factor 3), FKHR (forkhead in rhabdomyosarcoma)] in vitro, while insulin promotes the phosphorylation and inactivation of FKHR in a phosphatidylinositol 3-kinase- and protein kinase B (PKB)-dependent manner. This mechanism has been proposed to underlie insulin action on G6Pase and IGFBP-1 gene transcription. However, we find that treatment of cells with phorbol esters mimics the effect of insulin on G6Pase, but not IGFBP-1, gene expression. Indeed, phorbol ester treatment actually blocks the ability of insulin to repress IGFBP-1 gene expression. In addition, the action of phorbol esters is significantly reduced by inhibition of the p42/p44 mitogen-activated protein (MAP) kinase pathway. However insulin-induced phosphorylation of PKB or FKHR is not affected by the presence of phorbol esters. Therefore we suggest that activation of p42/p44 MAP kinases will reduce the sensitivity of the IGFBP-1 gene promoter, but not the G6Pase gene promoter, to insulin. Importantly, the activation of PKB and phosphorylation of FKHR is not, in itself, sufficient to reduce IGFBP-1 gene expression in the presence of phorbol esters.

scholarly journals Insulin-Like Growth Factor Binding Protein-3 Exerts Its Anti-Metastatic Effect in Aerodigestive Tract Cancers by Disrupting the Protein Stability of Vimentin

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1041
Author(s):  
Huong Thuy Le ◽  
Ho Jin Lee ◽  
Jaebeom Cho ◽  
Hye-Young Min ◽  
Ji-Sun Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Stability ◽  
Binding Protein ◽  
Migration And Invasion ◽  
Insulin Like Growth Factor ◽  
Factor Binding ◽  
Local Invasion ◽  
Igfbp 3

The proapoptotic, antiangiogenic, and antimetastatic activities of insulin-like growth factor binding protein-3 (IGFBP-3) through IGF-dependent or -independent mechanisms have been suggested in various types of human cancers. However, a mechanistic explanation of and downstream targets involved in the antimetastatic effect of IGFBP-3 is still lacking. In this study, by applying various in vitro and in vivo models, we show that IGFBP-3 suppresses migration and invasion of human head and neck squamous carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cells. Silencing IGFBP-3 expression elevated the migration and invasion of NSCLC and HNSCC cells in vitro and their local invasion and metastasis in vivo, whereas overexpression of IGFBP-3 decreased such prometastatic changes. Local invasion of 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC tumors was consistently significantly potentiated in Igfbp3 knockout mice compared with that in wild-type mice. Mechanistically, IGFBP-3 disrupted the protein stability of vimentin via direct binding and promoting its association with the E3 ligase FBXL14, causing proteasomal degradation. The C-terminal domain of IGFBP-3 and the head domain of vimentin are essential for their interaction. These results provide a molecular framework for IGFBP-3′s IGF-independent antimetastatic and antitumor activities.

scholarly journals Insulin-Like-Growth-Factor-Binding-Protein-3 (IGFBP-3) Contrasts Melanoma Progression In Vitro and In Vivo

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e98641 ◽  
Author(s):  
Antimo Naspi ◽  
Vincenzo Panasiti ◽  
Franco Abbate ◽  
Vincenzo Roberti ◽  
Valeria Devirgiliis ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Factor Binding ◽  
Melanoma Progression ◽  
Igfbp 3
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