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Biological effects of human insulin receptor substrate‐1 overexpression in hepatocytes
Author(s) -
Tanaka S,
Mohr L,
Schmidt E V,
Sugimachi K,
Wands J R
Publication year - 1997
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510260310
Subject(s) - signal transducing adaptor protein , signal transduction , protein kinase b , mapk/erk pathway , biology , pi3k/akt/mtor pathway , cancer research , grb2 , microbiology and biotechnology , chemistry
The human insulin receptor substrate‐1 (hIRS‐1) is a key intracellular protein involved in various cytokine signaling pathways associated with cell growth. We have previously demonstrated that stable transfection and overexpression of hIRS‐1 in human hepatoblastoma cells in vitro leads to the constitutive activation of the mitogen‐activated protein kinase (MAPK) cascade. In this setting, hIRS‐1 acts as a dominant oncogene and will induce neoplastic transformation of NIH 3T3 cells. In the present study, the biologic effects of hIRS‐1 overexpression in the liver was analyzed using both clinical tumor samples and a newly developed transgenic mouse model. We have found that approximately 40% of 22 human hepatocellular carcinoma (HCC) tumors had enhanced (>200%) hIRS‐1 gene expression compared with adjacent non‐involved liver tissue. There was a significant relationship between the level of hIRS‐1 overexpression and the tumor size; this finding suggests a possible role for hIRS‐1 in tumor progression. To determine if downstream signal transduction cascades were activated by overexpression of hIRS‐1 in hepatocytes, we established a transgenic mouse model using an hIRS‐1 construct driven by an albumin promoter/enhancer element to direct liver specific expression. The overexpressed hIRS‐1 protein was found to be tyrosyl phosphorylated and interacted with downstream SH2‐containing molecules such as the p85 subunit of phosphatidylinositol‐3 kinase (PI3K), Grb2 adaptor, and SHP2 phosphatase proteins. The functional consequences of hIRS‐1 overexpression were reflected by constitutive activation of both the MAPK and PI3K signal transduction cascades. More important, overexpression of hIRS‐1 in the transgenic liver led to increased hepatocyte DNA synthesis. Our findings indicate that hIRS‐1 overexpression induces downstream signaling molecules associated with hepatocyte growth and may potentially enhance tumor progression of HCC.