Aug 1, 1996

Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis

Cancer Research
S Tanaka, J R Wands

Abstract

Insulin-like growth factors initiate tyrosyl phosphorylation of the insulin receptor substrate I (IRS-I) protein and activate multiple signaling pathways essential for liver growth. This gene has been found to be up-regulated in human hepatocellular carcinomas (HCCs), and overexpression of IRS-1 in NIH 3T3 cells leads to malignant transformation with activation of the mitogen-activated protein kinase cascade. To explore another possible role of IRS-I in hepatocarcinogenesis, we examined the capability of transforming growth factor beta1 (TGF-beta1), a known negative regulator of hepatocyte growth, to induce programmed cell death in the context of IRS-I overexpression. Hep3B HCC cells were stably transfected with a retroviral vector containing the IRS-I gene. The overexpressed IRS-I protein was highly tyrosyl phosphorylated following insulin/insulin- like growth factor I stimulation and led to constitutive activation of downstream signal transduction molecules such as phosphatidylinositol-3 kinase and mitogen-activated protein kinase. Although parental Hep3B cells were sensitive to apoptosis, the Hep3B-IRS-I-transfected cells acquired resistance to TGF-beta1-induced programmed cell death. Our investigations suggest that IRS-I-me...Continue Reading

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Mentioned in this Paper

Multifunctional Calcium-Calmodulin-Dependent Protein Kinases
IRS1 protein, human
Transforming Growth Factor beta
Apoptosis, Intrinsic Pathway
Phosphatidylinositol 3-Kinases
Liver Carcinoma
Tgfb1
Insulin receptor substrate 1 protein
IRS1
TGFB1

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