P-67 海洋真菌由来のHDM2-p53複合体形成阻害物質(ポスター発表の部)

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Cellular events are regulated by the synthesis and degradation of regulatory proteins, and a defect in either process leads to the onset of various diseases. With respect to protein degradation, it is physiologically important for intracellular proteins to be timely degraded. The ubiquitin-proteasome pathway functions in selective degradation of intracellular proteins and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, immune response, and so on. Ubiquitin attaches to a target protein prior to degradation, which requires the sequential actions of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3). As E3 definitively determines which target proteins are polyubiquitinated, it can be inferred that specific inhibitors against E3 enzymes recognizing key target proteins could be good leads for therapy of the diseases connected with the turnover of the respective key target proteins. Among many E3s, MDM2, an E3 for p53 protein, is frequently used as a target for inhibitor development. MDM2 is normally expressed at a low level, while it is overexpressed in a variety of human cancers. p53 is a tumor suppressor that is mutated in more than 50% human cancers and this protein induces growth arrest and apoptosis upon activation by various stimuli such as DNA damage. Therefore, targeting MDM2 is a promising approach to reactivate p53, inducing apoptosis in human cancer cells. In this study, we report the isolation of a new inhibitor of HDM2-p53 interaction, (-)-hexylitaconic acid, from the culture broth of a marine-derived fungus, Arthrinium sp. Although several synthetic inhibitors of MDM2-p53 interaction have been reported so far, this is the second report on the inhibitor isolated from the natural resources.
天然有機化合物討論会の論文
2005-09-15

P-67 海洋真菌由来のHDM2-p53複合体形成阻害物質(ポスター発表の部)

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