PMID:21068752

Citation	Almeida, S, Ryser, S, Obarzanek-Fojt, M, Hohl, D and Huber, M (2011) The TRAF-interacting protein (TRIP) is a regulator of keratinocyte proliferation. J. Invest. Dermatol. 131:349-57
Abstract	The TRAF-interacting protein (TRIP/TRAIP) is a RING-type E3 ubiquitin ligase inhibiting tumor necrosis factor-α (TNF-α)-mediated NF-κB 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-κB activity in TRIP-KD keratinocytes, indicating that NF-κB activity in keratinocytes is not regulated by TRIP. TRIP expression was increased by ∼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.
Links	PubMed Online version:10.1038/jid.2010.329
Keywords	Carcinoma, Basal Cell/metabolism; Carcinoma, Basal Cell/pathology; Cell Cycle/physiology; Cell Differentiation/physiology; Cell Line; Cell Proliferation; Cells, Cultured; Female; HeLa Cells; Humans; Intermediate Filament Proteins/metabolism; Keratin-1/metabolism; Keratinocytes/cytology; Keratinocytes/physiology; Male; NF-kappa B/metabolism; Skin Neoplasms/metabolism; Skin Neoplasms/pathology; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/genetics; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:TRAIP		GO:0010838: positive regulation of keratinocyte proliferation	ECO:0000315:		P		BrdU incorporation was used to monitor cell proliferation and it was found that DNA synthesis in the TRAIP knockout cells were significantly reduced. Indicating that the knockout of TRAIP caused arrest in cell proliferation of the keratinocyte (Figure 1A).	complete CACAO 12169

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