EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer

Kolev, Vihren N.; Mandinova, Anna; Guinea-Viniegra, Juan; Hu, Bing; Lefort, Karine; Lambertini, Chiara; Neel, Victor A.; Dummer, Reinhard; Wagner, Erwin F.; Dotto, G. Paolo

doi:10.1038/ncb1750

Cited by 183 publications

(210 citation statements)

References 44 publications

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“…The EGF effect on density-dependent gene expression has been reported in the literature (31). For K1, a recent study shows that EGF suppresses K1 by repressing the expression of Notch 1, an important regulator of cell-fate decisions in the epidermis (33). Although the expression of K1 was not altered by TCDD treatment, the expression of FLG was significantly increased over density alone by TCDD.…”

Section: Discussionmentioning

confidence: 96%

EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes

Sutter

Yin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Fig. 4. Opposing effects of TCDD and EGF on differentiation of NHEKs. (A)NHEKs were grown to confluence, and basal medium, or medium with ␣-naphthoflavone (NF, 1 M) was added 24 h before treatment. CEs were isolated after treatment with either 0.1% DMSO or TCDD (10 nM) for 5 days. (B) NHEKs were grown to confluence, and basal medium with or without EGF (10 ng/mL) was added 24 h before treatment. CEs were isolated after treatment with either 0.1% DMSO or TCDD (10 nM) for 5 days. (C) NHEKs were grown to confluence, and basal medium, or medium with EGF (10 ng/mL), was added 24 h before treatment. CEs were isolated after treatment with either 0.1% DMSO or TCDD (10 nM) in the presence or absence of PD153035 (300 nM) for 5 days. (A-C) The values for CEs are a mean of triplicate samples Ϯ SD. (D-G) NHEKs were grown to a cell density of either 50% or 100% confluence before basal medium, or medium with EGF (10 ng/mL), was added for 24 h before treatment. Total mRNA was isolated after treatment with either control vehicle (0.1% DMSO) or TCDD (10 nM) for 24 h. Real-time PCR was used to determine the relative expression of each indicated gene (y axis). Levels of mRNA [mean (n ϭ 3) Ϯ SD] are expressed in units relative to the minimum, given a value of 1. (A-G) The a indicates that the value from treatment with TCDD is significantly different from the DMSO control; the b indicates that the value from cotreatment with TCDD and NF is significantly different from TCDD alone; the c indicates that the value from cotreatment with TCDD and EGF is significantly different from with TCDD alone; the d indicates that the value from treatment with TCDD, EGF, and PD153035 is significantly different from treatment with TCDD and EGF; and the e indicates that treatment with EGF is significantly different from DMSO control treatment. For each of these comparisons, P Յ 0.01 by Student's t test. Comparisons made in D-G are within the group grown to a cell density of 100% confluence.

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Section: Discussionmentioning

confidence: 96%

EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes

Sutter

Yin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…p53 is also an established cancer gene in CSCC 40, 41, 42 and HNSCC 43. Although p53 levels in cutaneous SCC are less characterized, somatic mutations of TP53 are frequently found in many typical tumors including CSCCs, which is then likely to compromise p53 function 44.…”

Section: Notch Signaling In Cutaneous Squamous Cell Carcinoma (Cscc)mentioning

confidence: 99%

“…It is frequently overexpressed in epithelial tumors 43, 51 and persistently activated in keratinocyte tumors 52. In primary human keratinocytes, EGFR signaling suppresses differentiation and enhances proliferation by negatively modulating NOTCH1 transcript and protein levels through p53 41 in a similar way to SFK, suggesting Notch's central role in CSCC development.…”

Section: Notch Signaling In Cutaneous Squamous Cell Carcinoma (Cscc)mentioning

confidence: 99%

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

et al. 2016

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The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro‐oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

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“…Likewise, in relation to early follicle development there are no reports of direct interaction between noggin, an important antagonist of BMP activity located in the mesenchyme and KGF and EGF signalling. However, it is interesting that the Notch pathway is linked to early follicle development (Favier et al, 2000) and that EGFR has been recently identified as a key negative regulator of notch1 gene expression in primary human keratinocytes (Kolev et al, 2008). It is also noteworthy that AP2α , which is a negative regulator of the EGF receptor (Wang et al, 2006), also becomes strongly expressed in the emerging HF placode (Panteleyev et al, 2003).…”

Section: Research Articlementioning

confidence: 99%

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

et al. 2009

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A key initial event in hair follicle morphogenesis is the localised thickening of the skin epithelium to form a placode, partitioning future hair follicle epithelium from interfollicular epidermis. Although many developmental signalling pathways are implicated in follicle morphogenesis, the role of epidermal growth factor (EGF) and keratinocyte growth factor (KGF, also known as FGF7) receptors are not defined. EGF receptor (EGFR) ligands have previously been shown to inhibit developing hair follicles; however, the underlying mechanisms have not been characterised. Here we show that receptors for EGF and KGF undergo marked downregulation in hair follicle placodes from multiple body sites, whereas the expression of endogenous ligands persist throughout hair follicle initiation. Using embryonic skin organ culture, we show that when skin from the sites of primary pelage and whisker follicle development is exposed to increased levels of two ectopic EGFR ligands (HBEGF and amphiregulin) and the FGFR2(IIIb) receptor ligand KGF, follicle formation is inhibited in a time-and dose-dependent manner. We then used downstream molecular markers and microarray profiling to provide evidence that, in response to KGF and EGF signalling, epidermal differentiation is promoted at the expense of hair follicle fate. We propose that hair follicle initiation in placodes requires downregulation of the two pathways in question, both of which are crucial for the ongoing development of the interfollicular epidermis. We have also uncovered a previously unrecognised role for KGF signalling in the formation of hair follicles in the mouse.

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EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer

Cited by 183 publications

References 44 publications

EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes

EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

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