Epidermal growth factor and transforming growth factor‐α mRNA in rat small intestine: In situ hybridization study

Dvořák, Bohuslav; Holubec, Hana; LeBouton, A. V.; Wilson, Jean M.; Koldovský, Otakar

doi:10.1016/0014-5793(94)00942-2

Cited by 27 publications

(8 citation statements)

References 45 publications

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“…In the mammalian intestinal epithelium, EGFR is highly expressed in intestinal stem cells (ISC) and transit amplifying cells (Yang et al, 2017). EGFR ligands, such as EGF, are released by Paneth cells and the mesenchyme and are required for the maintenance and proliferation of ISCs (Dvořák et al, 1994;Jardé et al, 2020;Poulsen et al, 1986). Ectopic activation of EGFR signalling in the intestine by luminal application or genetic overexpression of pathway ligands (Bongers et al, 2012;Kitchen et al, 2005;Marchbank et al, 1995), or deletion of the negative regulator leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1) (Powell et al, 2012;Wong et al, 2012), leads to elevated ISC proliferation.…”

Section: Introductionmentioning

confidence: 99%

RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

Nászai

Bellec

et al. 2020

Preprint

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SummaryRAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine, and the mechanisms of how they contribute to tumorigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine. We identify non-canonical roles of RAL GTPases, not as RAS effectors, but rather by acting upstream of RAS activation via induction of EGFR internalization. Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to impacting stem cell proliferation and damage-induced intestinal regeneration, this function of RAL GTPases drives EGFR-dependent tumorigenic growth in the intestine and in human mammary epithelium. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of EGFR-driven tissue homeostasis and malignant growth.

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Section: Introductionmentioning

confidence: 99%

RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

Nászai

Bellec

et al. 2020

Preprint

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“…However, no accurate quantification was performed. Earlier studies from our laboratory have shown the presence and cellular localization of both EGF and TGF‐α mRNAs in the small intestine of suckling and adult rats [24]. Using an in situ hybridization technique, we have shown that the intestinal crypt epithelium is the major site of EGF and TGF‐α transcripts in both suckling and adult rats.…”

Section: Discussionmentioning

confidence: 61%

“…Previously, we have reported cellular localization of EGF and TGF‐α mRNA transcripts in developing small intestine of rats using an in situ hybridization technique. However, an accurate quantification of these two mRNAs was not performed [24]. Since gene expression of these transcripts in developing small intestine is very low, the reverse transcription (RT) competitive‐polymerase chain reaction (PCR) assay has been established to amplify the messages and measure mRNA levels quantitatively.…”

Section: Introductionmentioning

confidence: 99%

The expression of epidermal growth factor and transforming growth factor‐α mRNA in the small intestine of suckling rats: organ culture study

et al. 1998

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Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are associated with regulation of various gastrointestinal functions. In order to better understand their role in developing small intestine EGF, TGF-alpha and EGF-R steady-state mRNA levels and transcript stability were determined. Reverse transcription (RT) competitive-polymerase chain reaction (PCR) revealed that intestinal TGF-alpha mRNA levels were 10-fold higher in comparison with EGF mRNA. The primary intestinal culture technique was used to evaluate mRNA stability. The stability of TGF-alpha mRNA was remarkably lower than the stability of EGF mRNA. High levels of TGF-alpha mRNA accompanied by high degradation rate of this mRNA suggested a rapid turnover of intestinal TGF-alpha mRNA.

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“…EGFR has seven known ligands (EGF, TGFα, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen). EGF is the most well-characterized ligand of EGFR and is expressed in Brunner’s glands of the duodenum and in Paneth cells in the lower gastrointestinal tract of adult rodents 35 , 36 . TGFα is abundantly expressed in uninjured intestinal crypts and villi and is thought to be the predominant EGFR ligand in the gastrointestinal tract 35 , 37 .…”

Section: Introductionmentioning

confidence: 99%

“…EGF is the most well-characterized ligand of EGFR and is expressed in Brunner’s glands of the duodenum and in Paneth cells in the lower gastrointestinal tract of adult rodents 35 , 36 . TGFα is abundantly expressed in uninjured intestinal crypts and villi and is thought to be the predominant EGFR ligand in the gastrointestinal tract 35 , 37 . Amphiregulin and epiregulin are expressed at low levels in human colonic mucosa, but demonstrate upregulated expression in IBD and prevent mucosal damage in rodent colitis 38 , 39 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice

Dubé

Liu

Girish

et al. 2018

Sci Rep

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Current treatments for inflammatory bowel disease (IBD) target the overactive immune response of the intestinal mucosa. However, epidermal growth factor (EGF), an activating ligand of the EGF receptor (EGFR), has been shown to induce disease remission through direct targeting of intestinal mucosal healing. Despite promising preclinical and clinical results, this EGFR-activating therapy has not progressed, in part due to the potential for carcinogenesis associated with long-term use and the increased risk of colitis-associated cancer (CAC) in IBD. Here we tested whether pharmacological modulation of EGFR altered outcomes of CAC in the murine azoxymethane/dextran sulfate sodium model. We found that administering EGF during the period of maximum colitis severity (“early”), coincident with the initiation and early promotion of tumors, improved outcomes of colitis and reduced tumor size. In contrast, daily EGF administration beginning ~2 months after tumor initiation (“late”) increased tumor size. Administration of the EGFR kinase inhibitor gefitinib increased the tumor size when the drug was given early and decreased the tumor size when the drug was administered late. EGF administration not only reduced colonic cytokine and chemokine expression during injury, but also baseline chemokine expression in homeostasis. These results suggest that EGFR activation during acute bouts of colitis may reduce the long-term burden of CAC.

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Epidermal growth factor and transforming growth factor‐α mRNA in rat small intestine: In situ hybridization study

Cited by 27 publications

References 45 publications

RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

RAL GTPases mediate EGFR-driven intestinal stem cell hyperproliferation and tumourigenesis

The expression of epidermal growth factor and transforming growth factor‐α mRNA in the small intestine of suckling rats: organ culture study

Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice

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