Multifaceted functions of the forkhead box transcription factors FoxO1 and FoxO3 in skin

Abstract

Background: The ubiquitously expressed forkhead box, class O (FoxO) transcription factors act as signaling integrators in extensive transcriptional networks, ensuring maintenance of cell and tissue homeostasis over time and in response to environmental challenges. Proteins whose biosynthesis is controlled through FoxOs fulfil key functions in antioxidant defense, metabolism, cell cycle regulation and apoptosis.

Scope of review: All four mammalian FoxO isoforms (FoxO1, FoxO3, FoxO4 and FoxO6) are expressed in skin but functions have been specified only for FoxO1 and FoxO3. This review provides an overview on the roles of FoxO1 and FoxO3 in the major types of skin cells: fibroblasts, keratinocytes and melanocytes.

Major conclusions: As expected because of their target genes, FoxOs are involved in counter-acting oxidative stress and in decisions on cell fate regarding apoptosis or senescence. However, their role in skin surpasses these rather obvious tasks: FoxO1 is part of signaling axes related to the control of epidermal morphogenesis and the pathogenesis of acne. FoxO3 dampens the biosynthesis of melanin in melanocytes; on the other hand, FoxO3 suppression in melanoma is associated with impaired apoptosis and increased metastatic potential of melanoma cells. Upon skin injury, a well-balanced and -timed up-regulation of FoxOs appears to support the healing process through affecting proliferation, migration and apoptosis of keratinocytes, fibroblasts and other cells accumulating at the wounded site.

General significance: FoxO1 and FoxO3 are discussed as homeostatic factors that influence morphogenesis, maintenance and repair processes in skin as well as the pathogenesis of disorders such as acne and skin cancer.

Keywords: Epidermis; IGF-1; Melanogenesis; UV; Wound healing; p63.