Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-02-19

AUTHORS

E A Rorke, G Adhikary, C A Young, R H Rice, P M Elias, D Crumrine, J Meyer, M Blumenberg, R L Eckert

ABSTRACT

Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased. RNA array analysis reveals reduced expression of mRNA encoding differentiation-associated cutaneous keratins, hair keratins and associated proteins, late cornified envelope precursors and filaggrin-related proteins; and increased expression of mRNA encoding small proline-rich proteins, protease inhibitors (serpins), S100 proteins, defensins and hyperproliferation-associated keratins. These findings suggest that AP1 factor inactivation in the suprabasal epidermal layers reduces expression of AP1 factor-responsive genes expressed in late differentiation and is associated with a compensatory increase in expression of early differentiation genes. More... »

PAGES

e1647-e1647

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cddis.2015.21

DOI

http://dx.doi.org/10.1038/cddis.2015.21

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1020914598

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25695600


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30 schema:description Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased. RNA array analysis reveals reduced expression of mRNA encoding differentiation-associated cutaneous keratins, hair keratins and associated proteins, late cornified envelope precursors and filaggrin-related proteins; and increased expression of mRNA encoding small proline-rich proteins, protease inhibitors (serpins), S100 proteins, defensins and hyperproliferation-associated keratins. These findings suggest that AP1 factor inactivation in the suprabasal epidermal layers reduces expression of AP1 factor-responsive genes expressed in late differentiation and is associated with a compensatory increase in expression of early differentiation genes.
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36 schema:keywords RNA array analysis
37 S100
38 S100 protein
39 activator protein-1 (AP-1) transcription factor
40 activity
41 analysis
42 array analysis
43 assembly
44 associated proteins
45 barrier integrity
46 barriers
47 biochemical changes
48 body secretions
49 body surface
50 c-Jun
51 changes
52 choreographed process
53 compensatory increase
54 controller
55 cornified envelope
56 cornified envelope precursor protein
57 defensins
58 desmosome formation
59 differentiation
60 differentiation genes
61 disease
62 display
63 dominant negative c-Jun
64 early differentiation genes
65 envelope
66 envelope precursor protein
67 envelope precursors
68 epidermal keratinocyte differentiation
69 epidermal keratins
70 epidermal layer
71 epidermis
72 epidermis displays
73 expression
74 expression of mRNA
75 factor activity
76 factor function
77 factors
78 filaggrin
79 filaggrin-related proteins
80 filaments
81 findings
82 formation
83 function
84 genes
85 granules
86 hair keratin
87 hyperproliferation-associated keratins
88 inactivation
89 incorporation
90 increase
91 inflammation-associated proteins
92 inhibitors
93 integrity
94 keratin
95 keratin filaments
96 keratinocyte differentiation
97 keratoderma
98 keratohyalin granules
99 key controller
100 lamellar body secretion
101 late differentiation
102 layer
103 life
104 linker
105 mRNA
106 mice
107 molecular changes
108 murine epidermis
109 perturbations
110 phenotype
111 precursor protein
112 precursors
113 present study
114 process
115 proline-rich proteins
116 protease inhibitors
117 protein
118 protein-1 transcription factor
119 proteome
120 proteomic studies
121 reduction
122 secretion
123 small proline-rich proteins
124 study
125 suprabasal epidermal layers
126 surface
127 transcription factor activity
128 transcription factor function
129 transcription factors
130 transglutaminase
131 types
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