Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis.
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-mediated signals may act as survival factors and protect against TGF-beta1-induced apoptosis in HCC; this phenomenon may contribute to hepatic oncogenesis.
Tanaka
S
S
Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Charlestown 02129, USA.
Wands
J R
JR
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D016212:Transforming Growth Factor beta; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017871:Calcium-Calmodulin-Dependent Protein Kinases