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• W1569203766 abstract "The INK4A tumour suppressor gene is negatively regulated by the Polycomb Group(PcG) complexes, which plays an important role in stem cell- and cancer biology.Polycomb Repressive Complex 1 (PRC1) members posterior sex comb protein BMI1and polycomb proteins CBX7 and CBX8 have been shown to be directly involved inrepression of INK4A and delay of senescence, whereas evidence from mouse geneticssuggests that polyhomeotic protein Ph2 is also required. However, it is still unknownwhy the mammalian PRC1 complex has so many possible permutations compared to thebasic system in Drosphila and how this relates to the regulation of a single target gene.The aim was therefore to define the requirement and function of the three humanpolyhomeotic members, HPH1, -2 and -3, for INK4A repression. It was found thatdepletion of all HPH proteins by shRNA-mediated knockdown in primary humanfibroblasts results in derepression of INK4A and premature senescence. In contrast,overexpression of HPH proteins leads to activation of INK4A accompanied by loss ofPRC1 binding and PcG-associated histone H3K27 trimethylation at the locus. Thesediametrically opposite findings suggest that a fine balance in HPH protein levels isrequired for PcG repression. Furthermore, biochemical investigation of the interactionbetween CBX and HPH proteins did not demonstrate any level of specificity, butemphasised the RNA binding capacity of both proteins, which was further investigated.In addition, by tandem affinity purification and mass spectrometry analysis it was foundthat HPH2 interacts with both PRC1 components and novel proteins, which werestudied for involvement in INK4A repression. In summary, this thesis demonstrates anessential role for the HPH proteins in the regulation of INK4A and provides novelinsights into their functional contribution to PcG repression." @default.
• W1569203766 created "2016-06-24" @default.
• W1569203766 creator A5008085919 @default.
• W1569203766 date "2010-07-28" @default.
• W1569203766 modified "2023-09-24" @default.
• W1569203766 title "The role of polyhomeotic in polycomb group-mediatedregulation of the tumour suppressor P16INK4A" @default.
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