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PMID: 16871158 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin.

The EMBO journal ·Vol. 25 ·No. 14 ·2006-07-26 ·Pages 3298-309

Williamson L, Raess NA, Caldelari R, Zakher A, de Bruin A, Posthaus H, Bolli R, Hunziker T, Suter MM, Müller EJ

Abstract

The autoimmune disease pemphigus vulgaris (PV) manifests as loss of keratinocyte cohesion triggered by autoantibody binding to desmoglein (Dsg)3, an intercellular adhesion molecule of mucous membranes, epidermis, and epidermal stem cells. Here we describe a so far unknown signaling cascade activated by PV antibodies. It extends from a transient enhanced turn over of cell surface-exposed, nonkeratin-anchored Dsg3 and associated plakoglobin (PG), through to depletion of nuclear PG, and as one of the consequences, abrogation of PG-mediated c-Myc suppression. In PV patients (6/6), this results in pathogenic c-Myc overexpression in all targeted tissues, including the stem cell compartments. In summary, these results show that PV antibodies act via PG to abolish the c-Myc suppression required for both maintenance of epidermal stem cells in their niche and controlled differentiation along the epidermal lineage. Besides a completely novel insight into PV pathogenesis, these data identify PG as a potent modulator of epithelial homeostasis via its role as a key suppressor of c-Myc.

MeSH Terms
Animals Cells, Cultured Humans Mice Mice, Inbred C57BL Mice, Knockout Pemphigus/genetics,metabolism Proto-Oncogene Proteins c-myc/antagonists & inhibitors,deficiency,genetics Repressor Proteins/genetics,physiology Skin/metabolism beta Catenin/deficiency,genetics gamma Catenin/genetics,physiology
Chemicals
Jup protein, mouse Myc protein, mouse Proto-Oncogene Proteins c-myc Repressor Proteins beta Catenin gamma Catenin
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Williamson Lina
Molecular Dermatology, Institute Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Raess Natalia A
Caldelari Reto
Zakher Anthony
de Bruin Alain
Posthaus Horst
Bolli Reinhard
Hunziker Thomas
Suter Maja M
Müller Eliane J
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7601224
Published
2006-07-26
Pages
3298-309
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1523185
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.emboj.7601224 PMC Full Text View journal details
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