泛素化與去泛素化在蛋白質後轉譯修飾扮演重要角色,決定了蛋白在細胞中的穩定性,活性及定位。 而近年來有大量研究顯示泛素連接酶(E3 ligase)以及去泛素酶(Deubiquitinating enzymes.DUBs)在泛素蛋白酶體系統中一旦失去平衡會導致疾病生成甚至促進癌症發展.而在我們先前的研究中，我們闡明了泛素特異性胜肽酶24(Ubiquitin-specific peptidase 24 ,USP24)這一種嶄新的去泛素化酶在肺癌發展中扮演了多重角色。透過激活EGFR訊息傳導路徑能使USP24在肺癌早期表現明顯地降低; 然而，其表現量卻能透過單核苷酸多態性（SNP）和RNA編輯在肺癌晚期增加。此外，在我們的酵母雙雜合結果中，我們發現USP24可能與多個溴結構域蛋白相互作用。並且在我們最近初步結果顯示，USP24蛋白不但可以與BRD2, BRD7 及BRG1蛋白作用並能進一步透過去泛素化增加BRD2的蛋白質穩定性，這意味著這些BET 蛋白可能是USP24的受質。 我們更發現USP24可能藉由其C端aa.1942-aa.2153 這個區段與溴結構域蛋白作用。 另外我們也發現溴結構域蛋白的Lysine 391/400的位置可能是被泛素化及USP24作用之處。 基於這些結果，我們推斷USP24可能藉由穩定溴結構域蛋白來穩定染色絲整修(chromatin remodeling)以及基因調控。因此我們構建了一個去除與溴結構域蛋白作用區域的USP24∆ a.a1942-2153，然後進而研究在肺癌進展中USP24與溴結構域蛋白交互作用下扮演的角色。初步結果顯示,USP24 失去了溴結構域蛋白作用區域a.a1942-2153, 會抑制細胞遷移的能力。 而由於溴結構域蛋白對於染色質相互作用,轉錄和選擇性剪接的調控非常重要，並且其與基因不穩定性和基因調控有相關，因此了解如何調節蛋白質穩定性的機制將有利於未來的癌症預防。

Ubiquitin carries out their function through attachment to the cellular protein and further alters their activity, localization and stability. Abundant of research has shown that E3 ligase and deubiquitinating enzyme are related to cancer formation and progression. In our previous studies, we elucidated Ubiquitin-specific peptidase 24 (USP24), a novel deubiquitinating enzyme, acts as multiple roles in lung cancer progression. USP24 level is decreased in the early stage of lung cancer through EGFR signalling pathway activation; however, is increased in the late stage of lung cancer through single nucleotide polymorphism (SNP) and RNA editing. Moreover, in our yeast two hybrid data, we found that USP24 might interact with multiple bromodomain-containing proteins including BRD2, BRD7 etc. In this study, we demonstrate that USP24 can interact with BRD2, BRD7 and BRG1 and further increase its protein stability by deubiquitinating. We further addressed the interacting region between USP24 and BRD2 and found that the C-terminal USP24 (aa.1942-aa.2153) could interact with the bromodomain of BRD2. Moreover, lysine 391/400 on BRD2 might be the ubiquitination as well as the USP24 targeting site. Based on these results, we suggest that USP24 might be involved in the chromatin remodelling and genes regulation through stabilizing the bromodomain-containing proteins. Hence, we constructed a truncated USP24 with deletion site at our suspected bromodomain-interacting region USP24 (a.a1941-a.a2153) and then studied the role of USP24 in interaction between USP24 and bromodomain-containing proteins in lung cancer progression. The preliminary results indicated that loss of interaction site with BETs protein in USP24 render loss of cell migration. As BRDs are important for chromatin interaction and regulation of transcription and alternative splicing and are involved in genomic instability and gene regulation, understanding the mechanism of how to regulate the protein stability will be beneficial for cancer prevention in the future.

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