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- W2247122373 abstract "Resistance to apoptosis is a hallmark of tumour cells. It constitutes an important clinical problem since chemotherapy and irradiation act primarily by inducing apoptosis. Compounds inhibiting proteasomal activity are able to selectively induce tumour cell apoptosis and a growing body of evidence suggests the up-regulation of NOXA (a BH3-only protein) upon proteasome inhibition to be one of the essential events. However, the underlying molecular mechanisms giving rise to the selective NOXA up-regulation in tumour cells is poorly understood. The current work shows that in cells susceptible to proteasome inhibition NOXA protein was significantly less stable and continuously degraded by the Ubiquitin-Proteasome System (UPS). Amongst others, the degradation of substrates by the UPS is regulated by E3-ubiquitin ligases and deubiquitylating enzymes (DUBs). In the current work UCH-L1 was identified as a responsible DUB of NOXA, which was epigenetically silenced in tumour cells susceptible to proteasome inhibition. UCH-L1 binds and stabilizes NOXA by removing the Lys48-linked polyubiquitin chains that normally mark NOXA for proteasomal degradation. In line with these observations, increased UCH-L1 expression correlated with increased NOXA protein expression inhuman melanoma and colorectal cancer patient samples. As one of the genesresponsive to genotoxic stress, NOXA has been considered as the BH3-only protein to be involved in the fine-tuning of apoptosis. Correspondingly, the current work demonstrates that UCH-L1 expression is important for DNA-damage induced apoptosis. Down-regulation of UCH-L1 results in decreased susceptibility to DNA damage-induced apoptosis accompanied by a decreased NOXA accumulation. Taken together, the current work identified UCH-L1 as an important component of the DNA damage response that impacts on the susceptibility of cancer cells toward chemotherapy by stabilizing NOXA." @default.
- W2247122373 created "2016-06-24" @default.
- W2247122373 creator A5037873514 @default.
- W2247122373 date "2012-03-15" @default.
- W2247122373 modified "2023-09-27" @default.
- W2247122373 title "Ubiquitin C-terminal hydrolase-L1 (UCH-L1) stabilizes NOXA and impacts on cancer chemosusceptibility" @default.
- W2247122373 hasPublicationYear "2012" @default.
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