在乳腺肿瘤中，UBR5与MYC共同扩增，并编码泛素连接酶，该酶限制MYC依赖性细胞凋亡。,Cancer Research

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在乳腺肿瘤中，UBR5与MYC共同扩增，并编码泛素连接酶，该酶限制MYC依赖性细胞凋亡。
Cancer Research ( IF 12.5 ) Pub Date : 2020-04-01 , DOI: 10.1158/0008-5472.can-19-1647
Xi Qiao _{1,

2,

3} , Ying Liu _{4,

5} , Maria Llamazares Prada ₆ , Aravind K Mohan ₇ , Abhishekh Gupta ₈ , Alok Jaiswal ₈ , Mukund Sharma _{1,

2,

3} , Joni Merisaari _{1,

2,

3} , Heidi M Haikala ₉ , Kati Talvinen ₂ , Laxman Yetukuri _{1,

8} , Joanna W Pylvänäinen ₁₀ , Juha Klefström ₉ , Pauliina Kronqvist ₂ , Annika Meinander ₇ , Tero Aittokallio _{8,

11} , Ville Hietakangas _{4,

5} , Martin Eilers ₆ , Jukka Westermarck _{1,

2}

Affiliation

Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
Institute of Biomedicine, University of Turku, Turku, Finland.
TuDMM Doctoral Programme, University of Turku, Turku, Finland.
Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Theodor Boveri Institute and Comprehensive Cancer Center, Mainfranken, Biocenter, University of Würzburg, Würzburg, Germany.
Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Research Programs Unit/Translational Cancer Medicine & HiLIFE, University of Helsinki, Helsinki, Finland.
Turku BioImaging, University of Turku and Åbo Akademi University, Turku, Finland.
Department of Mathematics and Statistics, University of Turku, Turku, Finland.

为了获得最大的致癌活性，需要严格控制细胞MYC蛋白的水平，以使其不会诱导细胞凋亡。在这里，我们展示了泛素连接酶UBR5如何作为分子变阻器来防止MYC蛋白的过度积累。UBR5泛素化MYC，其对MYC蛋白稳定性的影响独立于FBXW7。内源UBR5沉默诱导MYC蛋白表达和调节MYC目标基因。与果蝇UBR5（Hyd）的肿瘤抑制功能一致，Hyd抑制了翼状视盘的dMyc依赖性过度生长。相反，在癌细胞中，UBR5抑制了MYC依赖的引发治疗引起的细胞凋亡。与癌症直接相关，MYC和UBR5基因在MYC驱动的人类癌症中被共同扩增。在功能上通过UBR5 / MYC共扩增，UBR5抑制了p53突变乳腺癌细胞中MYC介导的凋亡。此外，单细胞免疫荧光分析表明UBR5和MYC在人类基底型乳腺癌组织中相互表达。总之，UBR5是一种新型MYC泛素连接酶，是MYC活性的内源变阻剂。在MYC扩增的和p53突变的乳腺癌细胞中，UBR5在抑制MYC介导的细胞凋亡引发和防止药物诱导的细胞凋亡中具有重要作用。

"点击查看英文标题和摘要"

UBR5 is co-amplified with MYC in breast tumors and encodes an ubiquitin ligase that limits MYC-dependent apoptosis.

For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC, and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (Hyd) in Drosophila, Hyd suppressed dMyc-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were co-amplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC co-amplification. Further, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis.

更新日期：2020-04-03

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