IGF-I production by adult rat hepatocytes is stimulated by transforming growth factor-alpha and transforming growth factor-beta1

Voci, Adriana; Arvigo, Marica; Massajoli, M.; Garrone, Simona; Bottazzi, C; Demori, Ilaria; Gallo, Gabriella

doi:10.1530/eje.0.1400577

Cited by 13 publications

(8 citation statements)

References 30 publications

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“…Low concentrations stimulated ErbB2 expression at 72 h, but the highest doses inhibited it. The stimulatory effect of TGF-␤ 1 on ErbB2 levels at low concentrations may relate to its ability to induce IGF-1 expression (34), which we have shown also induces ErbB2 (data not shown). Cells treated with the highest doses of TGF-␤ 1 were apoptotic and likely unable to synthesize a normally induced protein, such as ErbB2.…”

Section: Hepatocytes Show Increased Protein Tyrosine Phosphorylation mentioning

confidence: 72%

The emergence of ErbB2 expression in cultured rat hepatocytes correlates with enhanced and diversified EGF-mediated signaling

Scheving

Zhang²,

Stevenson³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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The proliferative effects of EGF in liver have been extensively investigated in cultured hepatocytes. We studied the effects of EGF, insulin, and other growth regulators on the expression, interaction, and signaling of ErbB receptors in primary cultures of adult rat hepatocytes. Using immunological methods and ErbB tyrosine kinase inhibitors, we analyzed the expression and signaling patterns of the ErbB kinases over 120 h of culture. Basal and EGF-stimulated protein tyrosine phosphorylation increased as cells adapted in vitro. EGF receptor (EGFr) expression declined in the first 24 h, whereas ErbB3 expression rose. Although ErbB2 was not present in freshly isolated hepatocytes, EGF and insulin independently induced ErbB2 while suppressing ErbB3 expression. Low concentrations of EGF and insulin synergistically stimulated ErbB2 expression and DNA synthesis. The greatest increase in ErbB2, which is normally expressed by fetal and neonatal hepatocytes, occurred shortly before the onset of DNA synthesis (> 40 h). EGF promoted EGFr and ErbB2 coassociation, stimulating tyrosine phosphorylation of both proteins. In contrast, heregulin beta1 (HRG-beta1) did not promote ErbB2 and ErbB3 coassociation. A selective tyrphostin inhibitor of ErbB2 suppressed EGF-stimulated DNA synthesis, but maximum suppression required the blockade of the EGFr kinase as well. Maximal EGF stimulation of DNA synthesis in vitro depends on the induction of ErbB2 and involves an EGFr-ErbB2 heterodimer. The ability of insulin to induce ErbB2 suggests both a mechanism for the synergy between insulin and EGF and a possible metabolic control of ErbB2 in vivo.

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Section: Hepatocytes Show Increased Protein Tyrosine Phosphorylation mentioning

confidence: 72%

The emergence of ErbB2 expression in cultured rat hepatocytes correlates with enhanced and diversified EGF-mediated signaling

Scheving

Zhang²,

Stevenson³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…This would argue for involvement of the type II IGF-R, also known as the cation-independent mannose 6 phosphate receptor, involved in intracellular trafficking (68) as opposed to the type I IGF-R, which can be activated by insulin at the concentrations used in our assays (69). Previous studies have reported that TGF-␤ can induce IGF synthesis (70,71), which we believe explains the lack of an absolute requirement for IGF in TGF-␤-activated cells compared with CTGF-treated cells. In this manner, TGF-␤ induces the expression of multiple growth factors that are required for the completion of the developmental program.…”

Section: Discussionmentioning

confidence: 92%

Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation

Grotendorst¹,

Rahmanie²,

Duncan³

2004

FASEB j.

259

230

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Fibroblast proliferation, differentiation into myofibroblasts, and increased collagen synthesis are key events during both normal wound repair and fibrotic lesion formation. Here we report that these biological responses to TGF-beta by fibroblasts are regulated via a CTGF-dependent pathway in concert with either EGF or IGF-2. Our studies indicate these responses to TGF-beta are mutually exclusive, and cells that are proliferating do not express alpha-SMA or elevated levels of collagen synthesis. Cells expressing alpha-SMA do not exhibit DNA synthesis but do coexpress higher levels of types I and III collagen mRNA. Thus, fibroblast proliferation and differentiation are controlled by combinatorial signaling pathways involving not only components of the TGF-beta/CTGF pathway, but also signaling events induced by EGF and IGF-2-activated receptors. Collectively, our studies indicate TGF-beta functions as a classic embryonic inducer, initiating a cascade that is controlled by other factors in the cellular environment. We propose a model for this process with regard to wound repair and fibrotic lesion formation that is likely applicable to other instances of CTGF action during embryogenesis.

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“…EGF stimulates the production of IGF-I and IGFBP in cultured hepatocytes from adult rats [53]. TGF-a and TGF-b stimulate IGF-I and IGFBP secretion by cultured rat hepatocytes although no change in the abundance of IGF-I and IGFBP mRNA was observed [54]. Furthermore, type I IGF receptors, which are considered responsible for IGF-I-induced mitogenic action, are not present in cultured adult rat hepatocytes [13].…”

Section: Discussionmentioning

confidence: 99%

Suppression of transforming growth factor-β results in upregulation of transcription of regeneration factors after chronic liver injury

Nakamura

Ueno

Sakamoto

et al. 2004

Journal of Hepatology

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IGF-I production by adult rat hepatocytes is stimulated by transforming growth factor-alpha and transforming growth factor-beta1

Cited by 13 publications

References 30 publications

The emergence of ErbB2 expression in cultured rat hepatocytes correlates with enhanced and diversified EGF-mediated signaling

The emergence of ErbB2 expression in cultured rat hepatocytes correlates with enhanced and diversified EGF-mediated signaling

Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation

Suppression of transforming growth factor-β results in upregulation of transcription of regeneration factors after chronic liver injury

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