Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis

Hosur, Vishnu; Low, Benjamin E.; Shultz, Leonard D.; Wiles, Michael V.

doi:10.1242/bio.026260

Cited by 15 publications

(28 citation statements)

References 11 publications

(28 reference statements)

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“…Additionally, cancer cells overexpressing AREG can induce neoplastic transformation of neighboring cells through paracrine or endocrine activity . Also, more recently, we showed in mice that AREG underlies the hyperproliferative skin disease tylosis and that loss of AREG restores the normal skin phenotype in a mouse model of human tylosis . Together, these studies highlight the key role of AREG in several pathological processes, and the potential of AREG depletion as a therapeutic approach in multiple diseases.…”

Section: Discussionmentioning

confidence: 63%

ADAM17 is essential for ectodomain shedding of the EGF‐receptor ligand amphiregulin

et al. 2018

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The epidermal growth factor (EGF)‐receptor ligand amphiregulin (AREG) is a potent growth factor implicated in proliferative skin diseases and in primary and metastatic epithelial cancers. AREG, synthesized as a propeptide, requires conversion to an active peptide by metalloproteases by a process known as ectodomain shedding. Although (ADAM17) a disintegrin and metalloprotease 17 is a key sheddase of AREG, ADAM8‐, ADAM15‐, and batimastat (broad metalloprotease inhibitor)‐sensitive metalloproteases have also been implicated in AREG shedding. In the present study, using a curly bare (Rhbdf2cub) mouse model that shows loss‐of‐hair, enlarged sebaceous gland, and rapid cutaneous wound‐healing phenotypes mediated by enhanced Areg mRNA and protein levels, we sought to identify the principal ectodomain sheddase of AREG. To this end, we generated Rhbdf2cub mice lacking ADAM17 specifically in the skin and examined the above phenotypes of Rhbdf2cub mice. We find that ADAM17 deficiency in the skin of Rhbdf2cub mice restores a full hair coat, prevents sebaceous gland enlargement, and impairs the rapid wound‐healing phenotype observed in Rhbdf2cub mice. Furthermore, in vitro, stimulated shedding of AREG is abolished in Rhbdf2cub mouse embryonic keratinocytes lacking ADAM17. Thus, our data support previous findings demonstrating that ADAM17 is the major ectodomain sheddase of AREG.

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Section: Discussionmentioning

confidence: 63%

ADAM17 is essential for ectodomain shedding of the EGF‐receptor ligand amphiregulin

et al. 2018

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“…Furthermore, it indicates an altered localization of RHBDF2 in both tylotic and sporadic squamous cell esophageal tumors (3). Substantial evidence suggests that RHBDF2 regulates the EGFR signaling pathway and its downstream signaling events, including development of tylosis and epithelial tumorigenesis, through an enhanced secretion of the EGFR ligand amphiregulin (AREG) (9,10,11). It indicates a tissue-specific role of the RHBDF2-AREG-ADAM17-EGFR pathway in TOC, using mouse models (9,11).…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing Identified a Novel Mutation of the RHBDF2 Gene in a Chinese Family of Tylosis with Esophageal Cancer

Qu¹,

Sha²,

Zou³

et al. 2019

Acta Derm Venerol

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“…Additionally, cancer cells overexpressing AREG can induce neoplastic transformation of neighboring cells through paracrine or endocrine activity [30]. Also, more recently, we showed in mice that AREG underlies the hyperproliferative skin disease tylosis, and that loss of AREG restores the normal skin phenotype in a mouse model of human tylosis [31]. Together, these studies highlight the key role of AREG in several pathological processes, and the potential of AREG depletion as a therapeutic approach in multiple diseases.…”

Section: Discussionmentioning

confidence: 74%

ADAM17 is the Principal Ectodomain Sheddase of the EGF-Receptor Ligand Amphiregulin

Hosur

Farley

Burzenski

et al. 2017

Preprint

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The epidermal growth factor (EGF)-receptor ligand amphiregulin (AREG) is a potent growth factor implicated in proliferative skin diseases and in primary and metastatic epithelial cancers. AREG in vitro, synthesized as a pro-peptide, requires conversion to an active peptide by metalloproteases by a process known as ectodomain shedding. Although, (Adam17) a disintegrin and metalloprotease 17 is implicated in ectodomain shedding of AREG, it remains to be established in vivo whether ADAM17 contributes to AREG shedding. In the present study, using a curly bare (Rhbdf2 cub ) mouse model that shows loss-of-hair, enlarged sebaceous glands, and rapid cutaneous wound-healing phenotypes mediated by enhanced Areg mRNA and protein levels, we sought to identify the principal ectodomain sheddase of AREG. To this end, we generated Rhbdf2 cub mice lacking ADAM17 specifically in the skin and examined the above phenotypes of Rhbdf2 cub mice. We find that ADAM17 deficiency in the skin of Rhbdf2 cub mice restores a full hair coat, prevents sebaceous-gland enlargement, and impairs the rapid wound-healing phenotype observed in Rhbdf2 cub mice. Furthermore, in vitro, stimulated shedding of AREG is abolished in Rhbdf2 cub mouse embryonic keratinocytes lacking ADAM17. Thus, our data demonstrate that ADAM17 is the major ectodomain sheddase of AREG.

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Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis

Cited by 15 publications

References 11 publications

ADAM17 is essential for ectodomain shedding of the EGF‐receptor ligand amphiregulin

ADAM17 is essential for ectodomain shedding of the EGF‐receptor ligand amphiregulin

Whole Exome Sequencing Identified a Novel Mutation of the RHBDF2 Gene in a Chinese Family of Tylosis with Esophageal Cancer

ADAM17 is the Principal Ectodomain Sheddase of the EGF-Receptor Ligand Amphiregulin

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