Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy

Department of Molecular & Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. .
Current pharmaceutical design (Impact Factor: 3.45). 11/2012; 19(18). DOI: 10.2174/1381612811319180009
Source: PubMed


Within the past decade, there has been a revolution in the types of drugs developed to treat cancer. Therapies that selectively target cancer-specific aberrations, such as kinase inhibitors, have made a dramatic impact on a subset of patients. In spite of these successes, there is still a dearth of treatment options for the vast majority of patients. Therefore, there is a need to design therapies with broader efficacy. The p53 tumor suppressor pathway is one of the most frequently altered in human cancers. However, about half of all cancers retain wild-type p53, yet through various mechanisms, the p53 pathway is otherwiseinactivated. Targeting this pathway forreactivation truly represents the "holy grail" in cancer treatment. Most commonly, destabilization of p53 by various components of ubiquitin-proteasome system, notably the ubiquitin ligase MDM2 and its partner MDMX as well as various deubiquitinating enzymes (DUBs), render p53 inert and unresponsive to stress signals. Reinstating its function in cancer has been a long sought-after goal. Towards this end, a great deal of work has been devoted to the development of compounds thateither interfere with the p53-MDM2 and p53-MDMX interactions, inhibit MDM2 E3 activity, or target individual DUBs. Here we review the current progress that has been made in the field, with a special emphasis on both MDM2 and DUB inhibitors. Developing inhibitors targeting the upstream of the p53 ubiquitination pathway will likely also be a valuable option.

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  • Current pharmaceutical design 11/2012; 19(18). DOI:10.2174/1381612811319180001 · 3.45 Impact Factor
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    ABSTRACT: Ovarian tumor domain-containing ubiquitin (Ub) aldehyde binding protein 1 (Otub1) regulates p53 stability and activity via non-canonical inhibition of the MDM2 cognate Ub-conjugating enzyme (E2) UbcH5. However, it is not clear how this activity of Otub1 is regulated in cells. Here we report that Otub1 is monoubiquitinated by UbcH5 in cells and in vitro, primarily at the lysine 59 and 109 residues. This monoubiquitination, in turn, contributes to the activity of Otub1 to suppress UbcH5. The lysine-free Otub1 mutant (Otub1K0) fails to be monoubiquitinated and is unable to suppress the Ub-conjugating activity of UbcH5 in vitro and the MDM2-mediated p53 ubiquitination in cells. Consistently, this mutant is unable to stabilize p53, induce apoptosis, and suppress cell proliferation. Overexpression of Otub1K0 inhibits DNA-damage induced apoptosis. Adding either Lys-59 or Lys-109 back to the Otub1K0 mutant restores the monoubiquitination of Otub1 and its function to stabilize and activate p53. We further show that UbcH5 preferentially binds to the monoubiquitinated Otub1 via Ub interaction with its backside donor Ub-interacting surface, suggesting that this binding interferes with the self-assembly of Ub-charged UbcH5 (UbcH5∼Ub) conjugates, which is critical for Ub transfer. Thus, our data reveal novel insights into the Otub1 inhibition of E2 wherein monoubiquitination promotes the interaction of Otub1 with UbcH5 and the function to suppress it.
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