PMID- 21068752 OWN - NLM STAT- MEDLINE DCOM- 20110310 LR - 20211203 IS - 1523-1747 (Electronic) IS - 0022-202X (Linking) VI - 131 IP - 2 DP - 2011 Feb TI - The TRAF-interacting protein (TRIP) is a regulator of keratinocyte proliferation. PG - 349-57 LID - 10.1038/jid.2010.329 [doi] AB - The TRAF-interacting protein (TRIP/TRAIP) is a RING-type E3 ubiquitin ligase inhibiting tumor necrosis factor-alpha (TNF-alpha)-mediated NF-kappaB activation. TRIP ablation results in early embryonic lethality in mice. To investigate TRIP function in epidermis, we examined its expression and the effect of TRIP knockdown (KD) in keratinocytes. TRIP mRNA expression was strongly downregulated in primary human keratinocytes undergoing differentiation triggered by high cell density or high calcium. Short-term phorbol-12-myristate-13-acetate (TPA) treatment or inhibition of phosphatidylinositol-3 kinase signaling in proliferative keratinocytes suppressed TRIP transcription. Inhibition by TPA was protein kinase C dependent. Keratinocytes undergoing KD of TRIP expression by lentiviral short-hairpin RNA (shRNA; T4 and T5) had strongly reduced proliferation rates compared with control shRNA. Cell cycle analysis demonstrated that TRIP-KD caused growth arrest in the G1/S phase. Keratinocytes with TRIP-KD resembled differentiated cells consistent with the augmented expression of differentiation markers keratin 1 and filaggrin. Luciferase-based reporter assays showed no increase in NF-kappaB activity in TRIP-KD keratinocytes, indicating that NF-kappaB activity in keratinocytes is not regulated by TRIP. TRIP expression was increased by approximately 2-fold in basal cell carcinomas compared with normal skin. These results underline the important role of TRIP in the regulation of cell cycle progression and the tight linkage of its expression to keratinocyte proliferation. FAU - Almeida, Stephanie AU - Almeida S AD - Service of Dermatology and Venereology, University Hospital Center and University of Lausanne, Lausanne, Switzerland. FAU - Ryser, Stephan AU - Ryser S FAU - Obarzanek-Fojt, Magdalena AU - Obarzanek-Fojt M FAU - Hohl, Daniel AU - Hohl D FAU - Huber, Marcel AU - Huber M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20101111 PL - United States TA - J Invest Dermatol JT - The Journal of investigative dermatology JID - 0426720 RN - 0 (FLG protein, human) RN - 0 (Filaggrin Proteins) RN - 0 (Intermediate Filament Proteins) RN - 0 (Keratin-1) RN - 0 (NF-kappa B) RN - 0 (Tumor Necrosis Factor Receptor-Associated Peptides and Proteins) SB - IM MH - Carcinoma, Basal Cell/metabolism/pathology MH - Cell Cycle/physiology MH - Cell Differentiation/physiology MH - Cell Line MH - *Cell Proliferation MH - Cells, Cultured MH - Female MH - Filaggrin Proteins MH - HeLa Cells MH - Humans MH - Intermediate Filament Proteins/metabolism MH - Keratin-1/metabolism MH - Keratinocytes/*cytology/*physiology MH - Male MH - NF-kappa B/metabolism MH - Skin Neoplasms/metabolism/pathology MH - Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/genetics/*physiology EDAT- 2010/11/12 06:00 MHDA- 2011/03/11 06:00 CRDT- 2010/11/12 06:00 PHST- 2010/11/12 06:00 [entrez] PHST- 2010/11/12 06:00 [pubmed] PHST- 2011/03/11 06:00 [medline] AID - S0022-202X(15)35167-8 [pii] AID - 10.1038/jid.2010.329 [doi] PST - ppublish SO - J Invest Dermatol. 2011 Feb;131(2):349-57. doi: 10.1038/jid.2010.329. Epub 2010 Nov 11.