최소 단어 이상 선택하여야 합니다.
최대 10 단어까지만 선택 가능합니다.
다음과 같은 기능을 한번의 로그인으로 사용 할 수 있습니다.
NTIS 바로가기생명과학회지 = Journal of life science, v.30 no.5, 2020년, pp.483 - 490
김동은 (계명대학교 의과대학 이비인후과교실) , 우선민 (계명대학교 의과대학 면역학교실) , 권택규 (계명대학교 의과대학 면역학교실)
The ubiquitin system uses ligases and deubiquitinases (DUBs) to regulate ubiquitin position on protein substrates and is involved in many biological processes which determine stability, activity, and interaction of the target substrate. DUBs are classified in six groups according to catalytic domain...
* AI 자동 식별 결과로 적합하지 않은 문장이 있을 수 있으니, 이용에 유의하시기 바랍니다.
핵심어 | 질문 | 논문에서 추출한 답변 |
---|---|---|
OTUB1의 non-canonical 활성 증가는 어떻게 항암효과를 나타내는가? | OTUB1은 다양한 암에서 발현이 높으며 canonical 경로 활성화를 통해 종양의 진행 및 전이 증진효과 뿐만 아니라, 항암제에 대한 저항성을 가지기 때문에 환자의 생존율이 감소하는 등 나쁜 예후를 나타낸다. 이와 다르게 OTUB1의 non-canonical 활성 증가는 종 양억제유전자로 잘 알려진 p53의 ubiquitination 억제를 통하여 안정화를 유지함으로써 암세포사멸 유도를 통한 항암효과를 나타낸다. 뿐만 아니라, OTUB1에 의한 DEPTOR 발현 증가로 autophagy 활성을 통한 암세포 증식 억제 효과가 나타난다 (Table 2). | |
OTUB1의 특징은 무엇인가? | OTU 그룹에 속하는 otubain 1 (OTUB1)은 다양한 암에서 발현이 높으며 세포사멸 및 증식, 전이, 항암제 내성을 조절한 다고 보고되었다[5, 24, 45]. 또한 OTUB1은 DUB의 정규적(canonical) 활성뿐만 아니라 E2 conjugating 효소에 결합하여 단백질 기질로 ubiquitin의 이동을 막는 비정규적(non-canonical) 활성도 가지고 있다[32]. 본 보고에서는 OTUB1의 canonical, non-canonical 활성 조절에 따른 다양한 신호전달경로에서 OTUB1의 역할에 대해 기술하고자 한다. | |
OTUB1의 canonical과 non-canonical 경로는 각각 어떤 작용을 하는가? | 탈유비퀴틴화효소 중 OTU 그룹에 속하는 otubain 1 (OTUB1)은 다른 탈유비퀴틴화효소와 달리 canonical과 non-canonical 경로를 통해 OTUB1의 활성화를 유도하고 타겟 단백질의 ubiquitination을 억제함으로써 안정화를 유지시 킨다. Canonical 활성 경로의 경우 타겟 단백질에 부착된 ubiquitin chain을 직접적으로 절단하며, non-canonical 활성 경로의 경우 E2 conjugating 효소의 기능을 억제하고 타겟 단백질로 ubiquitin의 이동을 막는다(Fig. 2). |
Abdul Rehman, S. A., Kristariyanto, Y. A., Choi, S. Y., Nkosi, P. J., Weidlich, S., Labib, K., Hofmann, K. and Kulathu, Y. 2016. MINDY-1 is a member of an evolutionarily conserved and structurally distinct new family of deubiquitinating enzymes. Mol. Cell 63, 146-155.
Altun, M., Kramer, H. B., Willems, L. I., McDermott, J. L., Leach, C. A., Goldenberg, S. J., Kumar, K. G., Konietzny, R., Fischer, R., Kogan, E., Mackeen, M. M., McGouran, J., Khoronenkova, S. V., Parsons, J. L., Dianov, G. L., Nicholson, B. and Kessler, B. M. 2011. Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chem. Biol. 18, 1401-1412.
Arkin, M. R., Tang, Y. and Wells, J. A. 2014. Small-molecule inhibitors of protein-protein interactions: Progressing toward the reality. Chem. Biol. 21, 1102-1114.
Arnst, J. L., Davies, C. W., Raja, S. M., Das, C. and Natarajan, A. 2013. High-throughput compatible fluorescence resonance energy transfer-based assay to identify small molecule inhibitors of amsh deubiquitinase activity. Anal. Biochem. 440, 71-77.
Baietti, M. F., Simicek, M., Abbasi Asbagh, L., Radaelli, E., Lievens, S., Crowther, J., Steklov, M., Aushev, V. N., Martinez Garcia, D., Tavernier, J. and Sablina, A. A. 2016. OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination. EMBO Mol. Med. 8, 288-303.
Balakirev, M. Y., Tcherniuk, S. O., Jaquinod, M. and Chroboczek, J. 2003. Otubains: A new family of cysteine proteases in the ubiquitin pathway. EMBO Rep. 4, 517-522.
Chen, J., Dexheimer, T. S., Ai, Y., Liang, Q., Villamil, M. A., Inglese, J., Maloney, D. J., Jadhav, A., Simeonov, A. and Zhuang, Z. 2011. Selective and cell-active inhibitors of the USP1/UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells. Chem. Biol. 18, 1390-1400.
Chen, Y., Wang, Y. G., Li, Y., Sun, X. X. and Dai, M. S. 2017. Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria. Oncotarget 8, 11053-11062.
D'Arcy, P., Wang, X. and Linder, S. 2015. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol. Ther. 147, 32-54.
Deshaies, R. J. and Joazeiro, C. A. 2009. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399-434.
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., Morrison, B. 3rd. and Stockwell, B. R. 2012. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 149, 1060-1072.
Edelmann, M. J., Kramer, H. B., Altun, M. and Kessler, B. M. 2010. Post-translational modification of the deubiquitinating enzyme otubain 1 modulates active rhoa levels and susceptibility to yersinia invasion. FEBS J. 277, 2515-2530.
Ernst, A., Avvakumov, G., Tong, J., Fan, Y., Zhao, Y., Alberts, P., Persaud, A., Walker, J. R., Neculai, A. M., Neculai, D., Vorobyov, A., Garg, P., Beatty, L., Chan, P. K., Juang, Y. C., Landry, M. C., Yeh, C., Zeqiraj, E., Karamboulas, K., Allali-Hassani, A., Vedadi, M., Tyers, M., Moffat, J., Sicheri, F., Pelletier, L., Durocher, D., Raught, B., Rotin, D., Yang, J., Moran, M. F., Dhe-Paganon, S. and Sidhu, S. S. 2013. A strategy for modulation of enzymes in the ubiquitin system. Science 339, 590-595.
Fagerberg, L., Hallstrom, B. M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., Habuka, M., Tahmasebpoor, S., Danielsson, A., Edlund, K., Asplund, A., Sjostedt, E., Lundberg, E., Szigyarto, C. A., Skogs, M., Takanen, J. O., Berling, H., Tegel, H., Mulder, J., Nilsson, P., Schwenk, J. M., Lindskog, C., Danielsson, F., Mardinoglu, A., Sivertsson, A., von Feilitzen, K., Forsberg, M., Zwahlen, M., Olsson, I., Navani, S., Huss, M., Nielsen, J., Ponten, F. and Uhlen, M. 2014. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibodybased proteomics. Mol. Cell. Proteomics 13, 397-406.
Finley, D., Ciechanover, A. and Varshavsky, A. 2004. Ubiquitin as a central cellular regulator. Cell 116, S29-32.
Gao, S., Alarcon, C., Sapkota, G., Rahman, S., Chen, P. Y., Goerner, N., Macias, M. J., Erdjument-Bromage, H., Tempst, P. and Massague, J. 2009. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling. Mol. Cell 36, 457-468.
Goncharov, T., Niessen, K., de Almagro, M. C., Izrael-Tomasevic, A., Fedorova, A. V., Varfolomeev, E., Arnott, D., Deshayes, K., Kirkpatrick, D. S. and Vucic, D. 2013. OTUB1 modulates c-IAP1 stability to regulate signalling pathways. EMBO J. 32, 1103-1114.
Hao, M., Weng, X., Wang, Y., Sun, X., Yan, T., Li, Y., Hou, L., Meng, X. and Wang, J. 2018. Targeting CXCR7 improves the efficacy of breast cancer patients with tamoxifen therapy. Biochem. Pharmacol. 147, 128-140.
Herhaus, L., Al-Salihi, M., Macartney, T., Weidlich, S. and Sapkota, G. P. 2013. OTUB1 enhances TGFbeta signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3. Nat. Commun. 4, 2519-2531.
Herhaus, L., Perez-Oliva, A. B., Cozza, G., Gourlay, R., Weidlich, S., Campbell, D. G., Pinna, L. A. and Sapkota, G. P. 2015. Casein kinase 2 (CK2) phosphorylates the deubiquitylase OTUB1 at ser16 to trigger its nuclear localization. Sci. Signal. 8, ra35.
Iglesias-Gato, D., Chuan, Y. C., Jiang, N., Svensson, C., Bao, J., Paul, I., Egevad, L., Kessler, B. M., Wikstrom, P., Niu, Y. and Flores-Morales, A. 2015. OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo. Mol. Cancer 14, 8-21.
Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P., Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N., Vissing, H., Sekido, Y., Minna, J., Borodovsky, A., Schultz, D. C., Wilkinson, K. D., Maul, G. G., Barlev, N., Berger, S. L., Prendergast, G. C. and Rauscher, F. J. 3rd. 1998. BAP1: A novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097-1112.
Juang, Y. C., Landry, M. C., Sanches, M., Vittal, V., Leung, C. C., Ceccarelli, D. F., Mateo, A. R., Pruneda, J. N., Mao, D. Y., Szilard, R. K., Orlicky, S., Munro, M., Brzovic, P. S., Klevit, R. E., Sicheri, F. and Durocher, D. 2012. OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function. Mol. Cell 45, 384-397.
Karunarathna, U., Kongsema, M., Zona, S., Gong, C., Cabrera, E., Gomes, A. R., Man, E. P., Khongkow, P., Tsang, J. W., Khoo, U. S., Medema, R. H., Freire, R. and Lam, E. W. 2016. OTUB1 inhibits the ubiquitination and degradation of FOXM1 in breast cancer and epirubicin resistance. Oncogene 35, 1433-1444.
Komander, D., Clague, M. J. and Urbe, S. 2009. Breaking the chains: Structure and function of the deubiquitinases. Nat. Rev. Mol. Cell Biol. 10, 550-563.
Komander, D. and Rape, M. 2012. The ubiquitin code. Annu. Rev. Biochem. 81, 203-229.
Koulich, E., Li, X. and DeMartino, G. N. 2008. Relative structural and functional roles of multiple deubiquitylating proteins associated with mammalian 26S proteasome. Mol. Biol. Cell 19, 1072-1082.
Kulathu, Y. and Komander, D. 2012. Atypical ubiquitylation - the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat. Rev. Mol. Cell Biol. 13, 508-523.
Li, Y., Sun, X. X., Elferich, J., Shinde, U., David, L. L. and Dai, M. S. 2014. Monoubiquitination is critical for ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (Otub1) to suppress UbcH5 enzyme and stabilize p53 protein. J. Biol. Chem. 289, 5097-5108.
Liu, T., Jiang, L., Tavana, O. and Gu, W. 2019. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7 A11. Cancer Res. 79, 1913-1924.
Makarova, K. S., Aravind, L. and Koonin, E. V. 2000. A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and chlamydia pneumoniae. Trends Biochem. Sci. 25, 50-52.
Nakada, S., Tai, I., Panier, S., Al-Hakim, A., Iemura, S., Juang, Y. C., O'Donnell, L., Kumakubo, A., Munro, M., Sicheri, F., Gingras, A. C., Natsume, T., Suda, T. and Durocher, D. 2010. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature 466, 941-946.
Nicastro, G., Menon, R. P., Masino, L., Knowles, P. P., McDonald, N. Q. and Pastore, A. 2005. The solution structure of the Josephin domain of ataxin-3: Structural determinants for molecular recognition. Proc. Natl. Acad. Sci. USA. 102, 10493-10498.
Nijman, S. M., Luna-Vargas, M. P., Velds, A., Brummelkamp, T. R., Dirac, A. M., Sixma, T. K. and Bernards, R. 2005. A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773-786.
Pinto-Fernandez, A. and Kessler, B. M. 2016. Dubbing cancer: Deubiquitylating enzymes involved in epigenetics, DNA damage and the cell cycle as therapeutic targets. Front. Genet. 7, 133-145.
Quesada, V., Ordonez, G. R., Sanchez, L. M., Puente, X. S. and Lopez-Otin, C. 2009. The Degradome database: mammalian proteases and diseases of proteolysis. Nucleic Acids Res. 37, D239-243.
Reyes-Turcu, F. E., Ventii, K. H. and Wilkinson, K. D. 2009. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu. Rev. Biochem. 78, 363-397.
Sato, Y., Yoshikawa, A., Yamagata, A., Mimura, H., Yamashita, M., Ookata, K., Nureki, O., Iwai, K., Komada, M. and Fukai, S. 2008. Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains. Nature 455, 358-362.
Sheng, C., Dong, G., Miao, Z., Zhang, W. and Wang, W. 2015. State-of-the-art strategies for targeting protein-protein interactions by small-molecule inhibitors. Chem. Soc. Rev. 44, 8238-8259.
Stanisic, V., Malovannaya, A., Qin, J., Lonard, D. M. and O'Malley, B. W. 2009. OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity. J. Biol. Chem. 284, 16135-16145.
Sun, X. X., Challagundla, K. B. and Dai, M. S. 2012. Positive regulation of p53 stability and activity by the deubiquitinating enzyme otubain 1. EMBO J. 31, 576-592.
Swatek, K. N. and Komander, D. 2016. Ubiquitin modifications. Cell Res. 26, 399-422.
Wang, Y., Zhou, X., Xu, M., Weng, W., Zhang, Q., Yang, Y., Wei, P. and Du, X. 2016. OTUB1-catalyzed deubiquitination of FOXM1 facilitates tumor progression and predicts a poor prognosis in ovarian cancer. Oncotarget 7, 36681-36697.
Wiener, R., Zhang, X., Wang, T. and Wolberger, C. 2012. The mechanism of OTUB1-mediated inhibition of ubiquitination. Nature 483, 618-622.
Xu, L., Li, J., Bao, Z., Xu, P., Chang, H., Wu, J., Bei, Y., Xia, L., Wu, P., Yan, K., Lu, B. and Cui, G. 2017. Silencing of OTUB1 inhibits migration of human glioma cells in vitro. Neuropathology 37, 217-226.
Xu, L., Lubkov, V., Taylor, L. J. and Bar-Sagi, D. 2010. Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr. Biol. 20, 1372-1377.
Yuan, L., Yuan, P., Yuan, H., Wang, Z., Run, Z., Chen, G., Zhao, P. and Xu, B. 2017. Mir-542-3p inhibits colorectal cancer cell proliferation, migration and invasion by targeting OTUB1. Am. J. Cancer Res. 7, 159-172.
Zhao, L., Wang, X., Yu, Y., Deng, L., Chen, L., Peng, X., Jiao, C., Gao, G., Tan, X., Pan, W., Ge, X. and Wang, P. 2018. OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR. J. Biol. Chem. 293, 4883-4892.
Zhou, H., Liu, Y., Zhu, R., Ding, F., Cao, X., Lin, D. and Liu, Z. 2018. OTUB1 promotes esophageal squamous cell carcinoma metastasis through modulating Snail stability. Oncogene 37, 3356-3368.
Zhou, Y., Jia, Q., Meng, X., Chen, D. and Zhu, B. 2019. ERRalpha regulates OTUB1 expression to promote colorectal cancer cell migration. J. Cancer 10, 5812-5819.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.