Insulin-like growth factors initiate tyrosyl phosphorylation of the insulin receptor substrate 1 (IRS-1) 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-1 in hepatocarcinogenesis, we examined the capability of transforming growth factor β1 (TGF-β1), a known negative regulator of hepatocyte growth, to induce programmed cell death in the context of IRS-1 overexpression. Hep3B HCC cells were stably transfected with a retroviral vector containing the IRS-1 gene. The overexpressed IRS-1 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-1-transfected cells acquired resistance to TGF-β1-induced programmed cell death. Our investigations suggest that IRS-1-mediated signals may act as survival factors and protect against TGF-β1-induced apoptosis in HCC; this phenomenon may contribute to hepatic oncogenesis.

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This work was supported by Grants CA-35711 and AA-02666 from the NIH.

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