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当代肿瘤药物靶点

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

YY1 OPB肽抗癌活性的表征

卷 19, 期 6, 2019

页: [504 - 511] 页: 8

弟呕挨: 10.2174/1568009618666181031153151

价格: $65

摘要

背景:阴阳1(YY1)的癌蛋白结合(OPB)结构域由G201和S226之间的26个氨基酸组成,参与YY1与多种癌基因产物的相互作用,包括MDM2,AKT,EZH2和E1A。通过OPB结构域,YY1促进癌细胞中这些癌蛋白的致癌或增殖调节。我们以前证明具有OPB序列的肽阻断YY1-AKT相互作用并抑制乳腺癌细胞增殖。 目的:在目前的研究中,我们对OPB结构域进行了表征,并确定了肽设计的最小区域以抑制癌细胞。 方法:使用丙氨酸扫描方法,我们发现OPB C-末端的氨基酸是YY1与AKT结合所必需的。进一步的研究表明,OPB中的丝氨酸和苏氨酸残基而非赖氨酸在YY1-AKT相互作用中起关键作用。我们生成GFP融合表达载体以表达具有连续缺失的N末端的OPB肽,并发现OPB1(即G201-S226)是细胞质的,但OPB2(即E206-S226),OPB3(即E206-S226)和对照肽都是核和细胞质。 结果:OPB1和2均抑制乳腺癌细胞增殖和迁移,但OPB3表现出与对照相似的作用。 OPB1和2导致细胞周期停滞在G1期,增加p53和p21表达,并且降低MCF-7细胞中的AKT(S473)磷酸化,但在MDA-MB-231细胞中没有。 结论:总体而言,OPB的丝氨酸和苏氨酸对于YY1与癌蛋白的结合是必需的,并且OPB肽可以最小化为E206-S226,其维持对YY1促进的细胞增殖的抑制活性。

关键词: YY1,OPB肽,蛋白质相互作用,抑制活性,抗癌活性,癌蛋白。

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图形摘要

[1]
Zhang, Q.; Stovall, D.B.; Inoue, K.; Sui, G. The oncogenic role of Yin Yang 1. Crit. Rev. Oncog., 2011, 16, 163-197.
[2]
Zhang, Q.; Wan, M.; Shi, J.; Horita, D.A.; Miller, L.D.; Kute, T.E.; Kridel, S.J.; Kulik, G.; Sui, G. Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation. J. Mol. Cell Biol., 2016, 8, 232-243.
[3]
Sui, G. Affar el, B.; Shi, Y.; Brignone, C.; Wall, N.R.; Yin, P.; Donohoe, M.; Luke, M.P.; Calvo, D.; Grossman, S.R.; Shi, Y. Yin Yang. 1 is a negative regulator of p53. Cell, 2004, 117, 859-872.
[4]
Gronroos, E.; Terentiev, A.A.; Punga, T.; Ericsson, J. YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc. Natl. Acad. Sci. USA, 2004, 101, 12165-12170.
[5]
Hernandez-Munoz, I.; Taghavi, P.; Kuijl, C.; Neefjes, J.; van Lohuizen, M. Association of BMI1 with polycomb bodies is dynamic and requires PRC2/EZH2 and the maintenance DNA methyltransferase DNMT1. Mol. Cell. Biol., 2005, 25, 11047-11058.
[6]
Wilkinson, F.; Park, K.; Atchison, M.L. Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc. Natl. Acad. Sci. USA, 2006, 103, 19296-19301.
[7]
Wilkinson, F.; Pratt, H.; Atchison, M.L. PcG recruitment by the YY1 REPO domain can be mediated by Yaf2. J. Cell. Biochem., 2010, 109, 478-486.
[8]
Lee, J.S.; See, R.H.; Galvin, K.M.; Wang, J.; Shi, Y. Functional interactions between YY1 and adenovirus E1A. Nucleic Acids Res., 1995, 23, 925-931.
[9]
Lewis, B.A.; Tullis, G.; Seto, E.; Horikoshi, N.; Weinmann, R.; Shenk, T. Adenovirus E1A proteins interact with the cellular YY1 transcription factor. J. Virol., 1995, 69, 1628-1636.
[10]
Zhou, Q.; Engel, D.A. Adenovirus E1A243 disrupts the ATF/CREB-YY1 complex at the mouse c-fos promoter. J. Virol., 1995, 69, 7402-7409.
[11]
Cunningham, B.C.; Wells, J.A. High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science, 1989, 244, 1081-1085.
[12]
Trinh, R.; Gurbaxani, B.; Morrison, S.L.; Seyfzadeh, M. Optimization of codon pair use within the (GGGGS)3 linker sequence results in enhanced protein expression. Mol. Immunol., 2004, 40, 717-722.
[13]
Runnebaum, I.B.; Nagarajan, M.; Bowman, M.; Soto, D.; Sukumar, S. Mutations in p53 as potential molecular markers for human breast cancer. Proc. Natl. Acad. Sci. USA, 1991, 88, 10657-10661.
[14]
Shen, Y.; Maupetit, J.; Derreumaux, P.; Tuffery, P. Improved PEP-FOLD approach for peptide and miniprotein structure prediction. J. Chem. Theory Comput., 2014, 10, 4745-4758.
[15]
Yao, Y.L.; Yang, W.M.; Seto, E. Regulation of transcription factor YY1 by acetylation and deacetylation. Mol. Cell. Biol., 2001, 21, 5979-5991.
[16]
Deng, Z.; Wan, M.; Sui, G. PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. Mol. Cell. Biol., 2007, 27, 3780-3792.
[17]
Zhang, W.J.; Wu, X.N.; Shi, T.T.; Xu, H.T.; Yi, J.; Shen, H.F.; Huang, M.F.; Shu, X.Y.; Wang, F.F.; Peng, B.L.; Xiao, R.Q.; Gao, W.W.; Ding, J.C.; Liu, W. Regulation of transcription factor Yin Yang 1 by SET7/9-mediated lysine methylation. Sci. Rep., 2016, 6, 21718.
[18]
Rizkallah, R.; Hurt, M.M. Regulation of the transcription factor YY1 in mitosis through phosphorylation of its DNA-binding domain. Mol. Biol. Cell, 2009, 20, 4766-4776.
[19]
Zheng, H.; Chu, J.; Zeng, Y.; Loh, H.H.; Law, P.Y. Yin Yang 1 phosphorylation contributes to the differential effects of mu-opioid receptor agonists on microRNA-190 expression. J. Biol. Chem., 2010, 285, 21994-22002.
[20]
Hiromura, M.; Choi, C.H.; Sabourin, N.A.; Jones, H.; Bachvarov, D.; Usheva, A. YY1 is regulated by O-linked N-acetylglucosaminylation (O-glcNAcylation). J. Biol. Chem., 2003, 278, 14046-14052.
[21]
Jokela, T.A.; Makkonen, K.M.; Oikari, S.; Karna, R.; Koli, E.; Hart, G.W.; Tammi, R.H.; Carlberg, C.; Tammi, M.I. Cellular content of UDP-N-Acetylhexosamines controls hyaluronan synthase 2 expression and correlates with O-GlcNAc modification of transcription factors YY1 and SP1. J. Biol. Chem., 2011, 286, 33632-33640.
[22]
Ozcan, S.; Andrali, S.S.; Cantrell, J.E. Modulation of transcription factor function by O-GlcNAc modification. Biochim. Biophys. Acta, 2010, 1799, 353-364.
[23]
Griesenbeck, J.; Ziegler, M.; Tomilin, N.; Schweiger, M.; Oei, S.L. Stimulation of the catalytic activity of poly(ADP-ribosyl) transferase by transcription factor Yin Yang 1. FEBS Lett., 1999, 443, 20-24.
[24]
Palko, L.; Bass, H.W.; Beyrouthy, M.J.; Hurt, M.M. The Yin Yang-1 (YY1) protein undergoes a DNA-replication-associated switch in localization from the cytoplasm to the nucleus at the onset of S phase. J. Cell Sci., 2004, 117, 465-476.

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