Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation

Cuevas, Eva P.; Escribano, Óscar; Chiloeches, Antonio; Rubio, Sara; Domingo, Alberto; Fernández‐Moreno, María Dolores; Guijarro, Luis

doi:10.1016/j.jhep.2007.01.031

Cited by 33 publications

(42 citation statements)

References 25 publications

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“…IRS-4 knockdown in Ad5E1HEK293 cells also decreased the growth rate and proliferation (Figures 10b and c), implying that IRS-4 enhances growth/proliferation of Ad5E1-transformed human cells. Cell growth is similarly decreased in HepG2 cells when IRS-4 expression is decreased using siRNA (Cuevas et al, 2007). Phosphorylation levels of ERK 1 and ERK 2 were lower in A549Ad5E1A13S cells, and barely detected in Ad5E1HEK293 cells (Figure 9).…”

Section: Discussionmentioning

confidence: 89%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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Using mass spectrometric analysis insulin receptor substrate 4 (IRS-4) has been identified as a novel adenovirus 5 early region 1A (Ad5E1A)-binding protein. IRS-4 interacts with both the transcriptional activation domain (conserved region 3) and the N-terminal region of Ad5E1A13S. Prolonged expression of Ad5E1A13S is required for the observed dramatic increase in the levels of IRS-4 mRNA and protein in Ad5E1-transformed human cell lines. Once expressed, as well as binding to E1A and the insulin receptor, IRS-4 remains tyrosine phosphorylated and constitutively associates with the regulatory p85 subunit of phosphoinositide 3 kinase, resulting in the phosphorylation of Akt (causing activation) and GSK-3b (causing inhibition). Reducing IRS-4 expression using small interfering RNA (siRNA) in established Ad5E1A-expressing cell lines decreases the activation of Akt and cellular proliferation. During Ad5 infection, IRS-4 is not expressed. However, Ad5E1A associates with IRS-1, increasing Akt and GSK-3b phosphorylation and tyrosine phosphorylation of IRS-1 itself. We conclude that the association and altered regulation of IRS proteins by Ad5E1A contribute to the adenovirus-transformed phenotype and modulates viral infection in an Akt-dependent manner.

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Section: Discussionmentioning

confidence: 89%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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“…The notion that IRS4 is a constitutive active oncogenic protein primarily regulated transcriptionally also explains the recent observations that chromosomal translocation events can activate Irs4 expression, leading to T-cell acute lymphoblastic leukaemia3536 and subungual exostosis (a benign bone and cartilage producing tumour)37. In addition, in human hepatocellular carcinomas (HCC), IRS4 expression is frequently upregulated compared with hepatocytes38, and its role in this malignancy has been further substantiated in the HEPG2 hepatoblastoma cell line where IRS4 plays an important role in cell proliferation39. These findings suggest that IRS4 expression is highly relevant in various human cancers.…”

Section: Discussionmentioning

confidence: 89%

IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation

et al. 2016

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In search of oncogenic drivers and mechanisms affecting therapy resistance in breast cancer, we identified Irs4, a poorly studied member of the insulin receptor substrate (IRS) family, as a mammary oncogene by insertional mutagenesis. Whereas normally silent in the postnatal mammary gland, IRS4 is found to be highly expressed in a subset of breast cancers. We show that Irs4 expression in mammary epithelial cells induces constitutive PI3K/AKT pathway hyperactivation, insulin/IGF1-independent cell proliferation, anchorage-independent growth and in vivo tumorigenesis. The constitutive PI3K/AKT pathway hyperactivation by IRS4 is unique to the IRS family and we identify the lack of a SHP2-binding domain in IRS4 as the molecular basis of this feature. Finally, we show that IRS4 and ERBB2/HER2 synergistically induce tumorigenesis and that IRS4-expression confers resistance to HER2-targeted therapy. Taken together, our findings present the cellular and molecular mechanisms of IRS4-induced tumorigenesis and establish IRS4 as an oncogenic driver and biomarker for therapy resistance in breast cancer.

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“…In our study signal transduction factor IRS4 and GPER1 were upregulated by HIF-1 alpha more than 6.0-fold. As for IRS4 some researchers have found that it plays an important role in proliferation/differentiation of tumors and exerts its actions through ERK and p70S6K activation in a ras/raf/MEK1/2 and PI3K/Akt independent manner and in a PKC-dependent way [18]. The GPER1 gene (also known as GPR30) represents an alternative estrogen-responsive receptor, which is highly expressed in tumors where estrogen and progesterone receptors are downregulated and in high-risk tumor patients with lower survival rates[19].…”

Section: Discussionmentioning

confidence: 99%

The effects of HIF-1alpha on gene expression profiles of NCI-H446 human small cell lung cancer cells

Wan

Mei

et al. 2009

J Exp Clin Cancer Res

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BackgroundGene targeted therapy refers to any therapy focused on one of the many biological features of the tumor. Such features are mediated by specific genes that are involved in tumor metastasis, recurrence, poor response to chemotherapy and others. Hypoxia is an important pathognomonic feature of many malignant tumors including SCLC (small cell lung cancer). HIF-1alpha, which is induced by hypoxia, is the most important regulatory factor of many specific genes that can influence the biological features of tumors.MethodsIn this study, we tried to elucidate the changes in gene expression profiles of SCLC NCI-H446 cells mediated by HIF-1alpha. According to different treatments of cells, three experimental pairwise comparisons were designed: hypoxia group vs. control group, Ad5-HIF-1alpha group vs. Ad5 group, and Ad5-siHIF-1 alpha group Vs Ad5 group.ResultsResults from the analysis of gene expression profiles indicated that there were 65 genes upregulated and 28 genes downregulated more than two-fold in all three experimental pairwise comparisons. These genes were involved in transport, signal-transduction, cell adhesion/motility, growth factor/cytokines, transcription, inflammatory response, metabolic process, in addition to others. SOCS1, IGFBP5, IL-6 and STAT3 were also upregulated at protein level. SOCS1 could significantly induce apoptosis and suppress growth of NCI-H446 cells but HIF-1alpha could induce growth and suppress apoptosis.ConclusionsThrough this research, we are trying to find novel functional genes that are mediated by HIF-1alpha and provide the theoretical basis for new therapeutic targets. HIF-1 alpha maybe upregulate the expression of SOCS1 through mediation of STAT3 and IL-6. In addition, SOCS1 could significantly induce apoptosis and suppress growth of NCI-H446 cells. This was contrary to HIF-1alpha and it indicated that there might be an antagonism effect between HIF-1alpha and SOCS1 on regulating growth and apoptosis of NCI-H446 cells.

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Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation

Cited by 33 publications

References 25 publications

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation

The effects of HIF-1alpha on gene expression profiles of NCI-H446 human small cell lung cancer cells

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