Jun signalling in the epidermis: From developmental defects to psoriasis and skin tumors

Area of Science:

• Molecular Biology
• Cell Biology
• Dermatology

Background:

• Jun proteins (Jun, JunB, JunD) are core components of the activator protein-1 (AP-1) transcription factor complex.
• AP-1 activity, regulated by MAPK cascades, influences cell proliferation, differentiation, transformation, and apoptosis.
• Conditional knock-out models, especially in epidermis, are crucial for studying AP-1 in vivo due to embryonic lethality of some AP-1 knock-outs.

Purpose of the Study:

• To investigate the distinct roles of Jun and JunB proteins in keratinocyte biology and skin homeostasis.
• To elucidate the involvement of JunB/AP-1 in the pathogenesis of psoriasis.

Main Methods:

• Utilized conditional knock-out strategies in mouse models, focusing on the epidermis.
• Analyzed the effects of Jun and JunB on keratinocyte proliferation and differentiation.
• Examined patient samples and an inducible mouse model to study JunB/AP-1 down-regulation in psoriasis.

Main Results:

• Jun acts as a positive regulator of keratinocyte proliferation and differentiation, partly via epidermal growth factor receptor (EGFR) expression.
• JunB antagonizes keratinocyte and hematopoietic stem cell proliferation.
• Down-regulation of JunB/AP-1 in keratinocytes is an initiating event in psoriasis development.

Conclusions:

• Jun and JunB proteins play opposing roles in keratinocyte proliferation and differentiation.
• JunB deficiency is implicated in the etiology of psoriasis, characterized by hyperproliferation and altered cytokine expression.
• Understanding Jun/AP-1 dynamics is critical for both normal skin physiology and skin cancer development.