Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 361, Issue 1, Pages 33-36Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2007.06.104
Keywords
itch; p73; p63; p53 chemosensitivity; p53; E3 ligase; protein degradation; proteasome; drug discovery
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Funding
- MRC [MC_U132670600] Funding Source: UKRI
- Medical Research Council [MC_U132670600] Funding Source: Medline
- Medical Research Council [MC_U132670600] Funding Source: researchfish
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Itch is a member of the HECT family of ubiquitin E3 ligases, and regulates the stability of several proteins involved in response to genotoxic stress. We have previously shown that p73 and p63, two members of the p53 family of tumour suppressors, are targets for Itch-mediated ubiquitylation and degradation. Here, we show that depletion of Itch by RNA interference augments apoptosis upon treatment with chemotherapeutic drugs. We also show that cells with no functional p53 are more sensitive to Itch depletion, highlighting the importance that changes in levels of Itch may play in majority of cancers, where p53 is absent or mutated. Furthermore, reintroduction of Itch in fibroblasts obtained from Itch deficient mice results in reduced cell death upon DNA damage. Overall our findings suggest that inhibition of Itch potentiates the effect of chemotherapeutic drugs revealing the pharmacological potentials of targeting Itch for cancer therapy. (c) 2007 Elsevier Inc. All rights reserved.
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