Transcriptional profiling defines the roles of ERK and p38 kinases in epidermal keratinocytes

Abstract

Epidermal keratinocytes respond to extracellular influences by activating cytoplasmic signal transduction pathways that change gene expression. Using pathway-specific transcriptional profiling, we identified the genes regulated by two such pathways, p38 and ERK. These pathways are at the fulcrum of epidermal differentiation, proliferative and inflammatory skin diseases. We used SB203580 and PD98059 as specific inhibitors and Affymetrix Hu133Av2 microarrays, to identify the genes regulated after 1, 4, 24, and 48 h and compared them to genes regulated by JNK. Unexpectedly, inhibition of MAPK pathways is compensated by activation of the NFkappaB pathway and suppression of the DUSP enzymes. Both pathways promote epidermal differentiation; however, there is a surprising disconnect between the expression of steroid synthesis enzymes and differentiation markers. The p38 pathway induces the expression of extracellular matrix and proliferation-associated genes, while suppressing microtubule-associated genes. The ERK pathway induces nuclear envelope and mRNA splicing proteins, while suppressing steroid synthesis and mitochondrial energy production enzymes. Transcription factors SRY, c-FOS, and N-Myc are the principal targets of the p38 pathway, Elk-1 SAP1 and HLH2 of ERK, while FREAC-4, ARNT and USF are shared. The results suggest a list of targets potentially useful in therapeutic interventions in cutaneous diseases and wound healing.

Multiple transcription factor codes activate epidermal wound–response genes in Drosophila

“…It is known that mouse fos and jun paralogs are expressed in differentiating epidermis and up-regulated in wounded epidermal cells (45). Also, in the cells surrounding epidermal wounds, there is some genetic evidence that certain jun and fos paralogs regulate wound healing, although whether they act to accelerate or retard (or both) the process of wound healing is still unclear (46)(47)(48)(49).…”

p38 maintains E-cadherin expression by modulating TAK1–NF-κB during epithelial-to-mesenchymal transition

“…Moreover, Dorsal, a Drosophila homolog of p65 NF-B, has been shown to control the transcription of Snail and Twist during development and innate immunity in Drosophila (Furlong et al, 2001), indicating a role in the expression of Snail and bHLH factors; and p38 activity can, depending on the experimental conditions, enhance or limit NF-B function (Orr et al, 2005;Gazel et al, 2008). Pretreatment of MCs with SB203580 or BIRB 796 increased the intensity of NF-B nuclear staining induced by cytokine treatment (Fig.…”

Zinc Released from Injured Cells Is Acting via the Zn2+-sensing Receptor, ZnR, to Trigger Signaling Leading to Epithelial Repair

“…The response to Zn 2ϩ is mediated through a G␣ q -coupled receptor, GPR39, which activates PLC and the IP 3 pathway, similar to the ZnR-response in colonocytes and neurons (20,30,41 Our results demonstrate ZnR-dependent activation of the MAPK pathway in keratinocytic cells. Activation of this pathway triggers the majority of the early genes induced in a scratch model and is essential for wound healing (51)(52)(53). Interestingly, a long-lasting, marked increase in ERK1/2 phosphorylation was apparent following a brief exposure to Zn 2ϩ .…”