PKCη promotes a proliferation to differentiation switch in keratinocytes via upregulation of p27Kip1 mRNA through suppression of JNK/c-Jun signaling under stress conditions

T Hara,S Takahashi,M Miyazaki,F Hakuno,K Chida

doi:10.1038/cddis.2011.40

Abstract

To maintain epidermal homeostasis, the balance between keratinocyte proliferation and differentiation is tightly controlled. However, the molecular mechanisms underlying this balance remain unclear. In 3D organotypic coculture with mouse keratinocytes and fibroblasts, the thickness of stratified cell layers was prolonged, and growth arrest and terminal differentiation were delayed when PKCη-null keratinocytes were used. Re-expression of PKCη in PKCη-null keratinocytes restored stratified cell layer thickness, growth arrest and terminal differentiation. We show that in 3D cocultured PKCη-null keratinocytes, p27Kip1 mRNA was downregulated, whereas JNK/c-Jun signaling was enhanced. Furthermore, inhibition of JNK/c-Jun signaling in PKCη-null keratinocytes led to upregulation of p27Kip1 mRNA, and to thinner stratified cell layers. Collectively, our findings indicate that PKCη upregulates p27Kip1 mRNA through suppression of JNK/c-Jun signaling. This results in promoting a proliferation to differentiation switch in keratinocytes.

Highlights

Changes in many processes, such as gene expression, control keratinocyte proliferation and differentiation.[2]
We used a 3D organotypic coculture system with primary mouse keratinocytes and fibroblasts that we have recently developed,[21] and we investigated the role of PKCZ on epidermal keratinocyte proliferation and differentiation
We provide evidence that PKCZ promotes keratinocytes to switch from proliferation to differentiation via the induction of p27Kip[1] mRNA through the suppression of JNK/c-Jun signaling

Summary

Introduction

Changes in many processes, such as gene expression, control keratinocyte proliferation and differentiation.[2]. Treatment and during re-epithelialization after skin injury.[12] PKCZ-null mice are susceptible to tumor formation via a two-stage skin carcinogenesis protocol; a single application of 7,12-dimethylbenz(a)anthracene for tumor initiation followed by TPA treatment for tumor promotion.[12] the regulation of keratinocyte proliferation, differentiation and tumor formation by PKCZ remains unclear and requires detailed study. The 3D organotypic coculture of keratinocytes with dermal fibroblasts can be used to induce stratification and to elucidate the molecular mechanisms underlying keratinocyte proliferation and differentiation, and to understand the interactions of keratinocytes with fibroblasts.[17] The 3D organotypic coculture is useful to understand re-epithelialization during wound healing.[18] many studies using human keratinocytes in 3D coculture have been reported, studies using genetically defined primary mouse keratinocytes and fibroblasts are

Methods

Results

Conclusion