scholarly journals Phosphatidylinositol 3-Kinase Is a Requirement for Insulin-Like Growth Factor I-Induced Differentiation, but not for Mitogenesis, in Fetal Brown Adipocytes

1997 ◽  
Vol 11 (5) ◽  
pp. 595-607 ◽  
Author(s):  
Angela M. Valverde ◽  
Margarita Lorenzo ◽  
Paloma Navarro ◽  
Manuel Benito
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Brown Adipocyte ◽  
Phosphatidylinositol 3 Kinase ◽  
Brown Adipocytes ◽  
Factor I ◽  
Kinase C ◽  
Igf I

Abstract In the present study we have examined the role of phosphatidylinositol 3-kinase (PI 3-kinase) in the insulin-like growth factor I (IGF-I)-signaling pathways involved in differentiation and in mitogenesis in fetal rat brown adipocytes. Activation of PI 3-kinase in response to IGF-I was markedly inhibited by two PI 3-kinase inhibitors (wortmannin and LY294002) in a dose-dependent manner. IGF-I-stimulated glucose uptake was also inhibited by both compounds. The expression of adipogenic-related genes such as fatty acid synthase, malic enzyme, glycerol 3-phosphate dehydrogenase, and acetylcoenzyme A carboxylase induced by IGF-I was totally prevented in the presence of IGF-I and any of those inhibitors, resulting in a marked decrease of the cytoplasmic lipid content. Moreover, the expression of the thermogenic marker uncoupling protein induced by IGF-I was also down-regulated in the presence of wortmannin/LY294002. IGF-I-induced adipogenic- and thermogenic-related gene expression was only partly inhibited by the p70S6k inhibitor rapamycin. In addition, pretreatment of brown adipocytes with either wortmannin or LY294002, but not with rapamycin, blocked protein kinase C ζ activation by IGF-I. In contrast, IGF-I-induced fetal brown adipocyte proliferation was PI 3-kinase-independent. Our results show for the first time an essential requirement of PI 3-kinase in the IGF-I-signaling pathways leading to fetal brown adipocyte differentiation, but not leading to mitogenesis. In addition, protein kinase C ζ seems to be a signaling molecule also involved in the IGF-I differentiation pathways downstream from PI 3-kinase.

scholarly journals Insulin-like effects of epidermal growth factor and insulin-like growth factor-I on [3H]2-deoxyglucose uptake, diacylglycerol generation and protein kinase C activation in BC3H-1 myocytes

1989 ◽  
Vol 261 (3) ◽  
pp. 927-934 ◽  
Author(s):  
R V Farese ◽  
G P Nair ◽  
C G Sierra ◽  
M L Standaert ◽  
R J Pollet ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Kinase C ◽  
Igf I ◽  
Epidermal Growth ◽  
Hydrolysis Of

Epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) were found to provoke increases in [3H]2-deoxyglucose uptake, diacylglycerol (DAG) generation and membrane-bound protein kinase C activity in BC3H-1 myocytes. These effects were similar to those provoked by insulin. The increases in DAG did not appear to be derived from hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) or phosphatidylinositol, but may have been derived from synthesis of phosphatidic acid de novo, and hydrolysis of phosphatidylcholine, as revealed by studies with [3H]glycerol and [3H]choline respectively. Accordingly, both EGF and IGF-I increased acute [3H]glycerol labelling of DAG (and other lipids) and [3H]choline labelling of phosphocholine. These labelling responses were similar in time course, suggesting that they are closely coupled. Our findings suggest that EGF and IGF-I, like insulin, increase DAG-protein kinase C signalling, apparently by activating co-ordinated lipid-synthesis and -hydrolysis responses, which are distinctly different from the PIP2-hydrolysis response.

scholarly journals Protein Kinase C-δ Is an Important Signaling Molecule in Insulin-Like Growth Factor I Receptor-Mediated Cell Transformation

1998 ◽  
Vol 18 (10) ◽  
pp. 5888-5898 ◽  
Author(s):  
Weiqun Li ◽  
Yi-Xing Jiang ◽  
Jiachang Zhang ◽  
Lilian Soon ◽  
Lawrence Flechner ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Transcriptional Activation ◽  
Cell Transformation ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Kinase C ◽  
Growth Factor I ◽  
Nih 3T3

ABSTRACT To investigate the potential role of protein kinase C-δ (PKC-δ) in insulin-like growth factor I receptor (IGF-IR)-mediated cell transformation, an oncogenic gag-IGF-IR β-fusion receptor lacking the entire extracellular domain, which was designated NM1, and a full-length IGF-IR were coexpressed with either wild-type PKC-δ (PKC-δWT) or an ATP-binding mutant of PKC-δ (PKC-δK376R) in NIH 3T3 fibroblasts. While overexpression of PKC-δWT did not affect NM1- and IGF-IR-induced focus and colony formation of NIH 3T3 cells, expression of PKC-δK376R severely impaired these events. In contrast, NM1-mediated cell growth in monolayer was not affected by coexpressing PKC-δK376R. PKC-δWT and PKC-δK376R were constitutively phosphorylated on a tyrosine residue(s) in the NM1- and IGF-IR-expressing cells and were associated with them in an IGF-I-independent manner. Activated IGF-IR was able to phosphorylate purified PKC-δ in vitro and stimulated its kinase activity. Furthermore, the level of endogenous PKC-δ protein was up-regulated through transcriptional activation in response to long-term IGF-IR activation. Taken together, our results demonstrate that PKC-δ plays an important role in IGF-IR-mediated cell transformation, probably via association of the receptor with PKC-δ and its activation through protein up-regulation and tyrosine phosphorylation. Competition with endogenous PKC-δ for NM1 and IGF-IR association by PKC-δK376R is probably an important mechanism underlying the PKC-δK376R-mediated inhibition of cell transformation by NM1 and IGF-IR.

scholarly journals Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyte primary cultures

1996 ◽  
Vol 319 (2) ◽  
pp. 627-632 ◽  
Author(s):  
Teresa TERUEL ◽  
Angela M VALVERDE ◽  
Manuel BENITO ◽  
Margarita LORENZO
Keyword(s):  
Growth Factor ◽  
Fatty Acid Synthase ◽  
Brown Adipocyte ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Brown Adipocytes ◽  
Factor I ◽  
Fetal Rat ◽  
Igf I ◽  
Growth Factor I

Fetal rat brown adipocytes show high-affinity binding sites for both insulin-like growth factor I (IGF-I) and insulin. Cell culture for 24 h in the presence of IGF-I or insulin, independently, up-regulated the mRNA expression of adipogenic-related genes, such as fatty acid synthase (FAS), glycerol-3-phosphate dehydrogenase and insulin-regulated glucose transporter Glut4, and down-regulated the expression of phosphoenolpyruvate carboxykinase mRNA in a dose-dependent manner. Moreover, both IGF-I and insulin increased the FAS gene transcription rate at 2 h, producing a time-dependent accumulation of FAS mRNA. Furthermore IGF-I or insulin increased glucose uptake and lipid content throughout the 24 h culture period. Our results suggest that both IGF-I and insulin are major signals involved in initiating and/or maintaining the expression of adipogenic-related genes in fetal rat brown adipocytes.

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