Transcriptional profiling defines the roles of ERK and p38 kinases in epidermal keratinocytes.
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.
Gazel
Alix
A
Department of Dermatology, The Cancer Institute, NYU School of Medicine, New York, New York 10016, USA. blumem01@med.nyu.edu
Nijhawan
Rajiv I
RI
Walsh
Rebecca
R
Blumenberg
Miroslav
M
D049109:Cell Proliferation; D002478:Cells, Cultured; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology*; D005109:Extracellular Matrix / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015603:Keratinocytes / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D046228:Microarray Analysis; D008870:Microtubules / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054637:Dual-Specificity Phosphatases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one