PMID- 18557926 OWN - NLM STAT- MEDLINE DCOM- 20090202 LR - 20191210 IS - 1600-0625 (Electronic) IS - 0906-6705 (Linking) VI - 17 IP - 12 DP - 2008 Dec TI - TNF-alpha stimulates Akt by a distinct aPKC-dependent pathway in premalignant keratinocytes. PG - 992-7 LID - 10.1111/j.1600-0625.2008.00740.x [doi] AB - Tumor necrosis factor-alpha (TNF-alpha) is an important proinflammatory cytokine involved in the pathogenesis of inflammatory skin diseases and cutaneous squamous cell carcinoma. Some of these effects are mediated by the stimulatory effect of this cytokine on the Akt signalling pathway, which renders keratinocytes less susceptible to proapoptotic stimuli and enhances cell growth. We have recently shown that TNF-alpha-induced Akt activation may promote the early stages of skin cancer. In this work, we demonstrate that in the premalignant keratinocyte cell line HaCaT, TNF-alpha activates Akt, ERK1/2 and p38. The specific peptide blocking the activity of the atypical protein kinase C (aPKC) species zeta and iota/lambda abrogated the effects of TNF-alpha on Akt and ERK1/2 but increased the activation of p38. The TNF-alpha-dependent phosphorylation of Akt-ERK1/2 was slightly decreased by NF kappaB inhibition and in the presence of p38 blockers. Akt/ERK signalling but not p38 activation was abolished in the presence of the iron chelator desferroxamine that blocks formation of hydroxyl ( OH) radicals. Thus, the TNF-alpha signalling in keratinocytes seems to bifurcate into an aPKC-, NFkB- and OH-dependent pathway resulting in the activation of survival and mitogenic pathways mediated by Akt and ERK1/2, and a signalling pathway conveyed by p38 that contributes to Akt activation but is suppressed by aPKC. Our data may be utilized in the development of more selective anti-TNF-alpha therapeutic strategies. FAU - Faurschou, Annesofie AU - Faurschou A AD - Department of Dermatology, University of Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark. af16@bbh.regionh.dk FAU - Gniadecki, Robert AU - Gniadecki R LA - eng PT - Journal Article DEP - 20080614 PL - Denmark TA - Exp Dermatol JT - Experimental dermatology JID - 9301549 RN - 0 (Androstadienes) RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Leupeptins) RN - 0 (Morpholines) RN - 0 (NF-kappa B) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Reactive Oxygen Species) RN - 0 (Tumor Necrosis Factor-alpha) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.13 (PKC-3 protein) RN - EC 2.7.11.13 (Protein Kinase C) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.4.22.- (Caspases) RN - J06Y7MXW4D (Deferoxamine) RN - R0ZB2556P8 (Tocopherols) RN - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde) RN - WYQ7N0BPYC (Acetylcysteine) RN - XVA4O219QW (Wortmannin) SB - IM MH - Acetylcysteine/pharmacology MH - Androstadienes/pharmacology MH - Apoptosis/drug effects MH - Blotting, Western MH - Caspases/metabolism MH - Cell Line MH - Cell Survival/drug effects MH - Chromones/pharmacology MH - Deferoxamine/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Humans MH - Keratinocytes/cytology/*drug effects/metabolism MH - Leupeptins/pharmacology MH - Morpholines/pharmacology MH - NF-kappa B/antagonists & inhibitors/metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylation/drug effects MH - Protein Kinase C/antagonists & inhibitors/*metabolism MH - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*metabolism MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/*drug effects MH - Tocopherols/pharmacology MH - Tumor Necrosis Factor-alpha/*pharmacology MH - Wortmannin MH - p38 Mitogen-Activated Protein Kinases/metabolism EDAT- 2008/06/19 09:00 MHDA- 2009/02/03 09:00 CRDT- 2008/06/19 09:00 PHST- 2008/06/19 09:00 [pubmed] PHST- 2009/02/03 09:00 [medline] PHST- 2008/06/19 09:00 [entrez] AID - EXD740 [pii] AID - 10.1111/j.1600-0625.2008.00740.x [doi] PST - ppublish SO - Exp Dermatol. 2008 Dec;17(12):992-7. doi: 10.1111/j.1600-0625.2008.00740.x. Epub 2008 Jun 14.