<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Regulation of MHC class I polypeptide related sequence B expression in melanoma cells under proteasome inhibition"^^ . "Malignant melanoma is a very aggressive tumor with a high metastatic potential and persistently increasing incidence rate. The low efficacy of conventional chemotherapy and radiation demands for the development of new approaches. Several new strategies take advantage of the strong intrinsic immunogenicity of the tumor that in principle allows autologous Natural killer (NK) cells and T cells to recognize and kill melanoma cells. One of the key receptors involved in the anti-tumor immunity is NKG2D, expressed on NK cells and CD8+ T cells. So far, eight surface ligands for this receptor have been identified in humans, belonging to the MIC and ULBP molecule families. Interaction of NKG2D with its surface ligands activates and costimulates the cytotoxic activity of NK cells and T cells, respectively. Expression of NKG2D ligands (NKG2DL) is known to be induced upon cell stress and moderate expression of NKG2DL can also be observed on tumor cells. Thus developing strategies that induce NKG2DL expression on tumor cells might be helpful to enhance anti-tumor immune responses, but as a prerequisite the mechanisms of NKG2DL regulation have to be elucidated. Proteasome inhibition causes so-called proteotoxic stress by an accumulation of unfolded proteins in the cell. As proteasome inhibitors are currently tested in melanoma therapy, the aim of the present study was to identify the impact of proteasome inhibition on NKG2DL expression in human melanoma cells. It was observed that treatment with the proteasome inhibitor MG132 strongly up-regulated the surface expression of the NKG2DL MICB on melanoma cells. Inhibitor treated cells contained elevated levels of MICB mRNA. MICB promoter driven luciferase reporter gene assays demonstrated that this up-regulation was dependent on transcription. Mutation of a heat shock factor 1 (HSF1) binding site within the MICB promoter region abrogated induction of transcription by MG132. Indeed, an enhanced binding of HSF1 to the MICB promoter in MG132 treated cells was demonstrated by chromatin immunoprecipitation (ChIP). Moreover, transfection of melanoma cells with a constitutively active HSF1 variant strongly stimulated MICB promoter driven reporter gene expression, whereas siRNA-mediated down-regulation of HSF1 blocked MICB induction upon proteasome inhibition. Interestingly, while over-expression of constitutive active HSF1 in the melanoma cells stimulated MICB promoter driven reporter gene expression, it did not enhance the transcription of endogenous MICB in melanoma cells, suggesting that under “normal conditions” HSF1 could not efficiently access the MICB promoter. Ubiquitination of histone H2A is known as an epigenetic mechanism of gene silencing. ChIP experiments demonstrated that ubiquitinated histone H2A is associated with the MICB promoter and that treatment of melanoma cells with MG132 resulted in a loss of H2A ubiquitination. This leads to the conclusion that proteasome inhibition elicits MICB expression by two events: down-regulation of the ubiquitination level of H2A, which controls promoter accessibility, and activation of HSF1 which then binds the MICB promoter and induces its transcription. "^^ . "2010" . . . . . . . . "Daria"^^ . "Vokhminova"^^ . "Daria Vokhminova"^^ . . . . . . "Regulation of MHC class I polypeptide related sequence B expression in melanoma cells under proteasome inhibition (PDF)"^^ . . . "Vokhminova_PhD_Thesis_FIN.pdf"^^ . . . "Regulation of MHC class I polypeptide related sequence B expression in melanoma cells under proteasome inhibition (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Regulation of MHC class I polypeptide related sequence B expression in melanoma cells under proteasome inhibition (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Regulation of MHC class I polypeptide related sequence B expression in melanoma cells under proteasome inhibition (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Regulation of MHC class I polypeptide related sequence B expression in melanoma cells under proteasome inhibition (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Regulation of MHC class I polypeptide related sequence B expression in melanoma cells under proteasome inhibition (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #11233 \n\nRegulation of MHC class I polypeptide related sequence B expression in melanoma cells under proteasome inhibition\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .