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首页> 外文期刊>Nature >The epichaperome is an integrated chaperome network that facilitates tumour survival
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The epichaperome is an integrated chaperome network that facilitates tumour survival

机译：Epiperperomeome是一个集成的伴侣网络，可促进肿瘤存活

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摘要

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery(1-6). Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy(7-17). As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.
机译：瞬时的多蛋白复合物是细胞功能的重要促进剂。其中包括分子伴侣，一个丰富的蛋白质家族，由分子伴侣，辅分子伴侣，衔接子和折叠酶-动力复合物组成，它们调节细胞稳态以及蛋白质降解机制（1-6）。许多研究已经探讨了伴侣分子在孤立中的作用，但关于它们在恶性肿瘤中如何相互作用和共同起作用的关系知之甚少（7-17）。由于功能可能高度依赖于天然肿瘤中发现的内源性条件，因此伴侣组拒绝进行研究，这主要是由于破坏或改造细胞环境以利于分析所需的方法的局限性。这种局限性导致我们对与伴侣组相关的疾病生物学的理解以及以伴侣组为目标的癌症治疗方法的发展成为瓶颈。在这里，我们检查了一大批肿瘤标本中的伴侣蛋白复合物。所使用的方法保持了肿瘤的内源性天然状态，我们利用它来研究癌症中分子伴侣的分子特征和组成，驱动分子伴侣网络在肿瘤中串扰的分子因素，分子伴侣对药理学敏感的区别因素。抑制，以及可能受益于伴侣治疗的肿瘤特征。我们发现，在应激条件下，例如MYC推动的恶性转化，分子伴侣被生化“重排”以形成稳定的，促进生存的高分子量复合物的网络。伴侣蛋白热激蛋白90（HSP90）和热激同源蛋白70（HSC70）是这些物理和功能整合的复合物的成核位点。结果表明，这些紧密整合的分子伴侣单元，这里称为表壳伴侣，可以起着提高细胞存活的网络的作用，而不论其来源组织或遗传背景如何。表壳组存在于所有测试的癌症的一半以上，不仅对诊断有影响，而且还具有潜在的脆弱性，可以作为药物干预的目标。

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  • 来源
    《Nature》 |2016年第7625期|397-401|共5页
  • 作者

    Rodina Anna; Wang Tai; Yan Pengrong; Gomes Erica DaGama; Dunphy Mark P. S.; Pillarsetty Nagavarakishore; Koren John III; Gerecitano John F.; Aldone Tony T.; Zong Hongliang; Caldas-Lopes Eloisi; Alpaugh Mary; Corben Adriana; Riolo Matthew; Beattie Brad; Pressl Christina; Peter Radu I.; Xu Chao; Trondl Robert; Patel Hardik J.; Shimizu Fumiko; Bolaender Alexander; Yang Chenghua; Panchal Palak; Farooq Mohammad F.; Kishinevsky Sarah; Modi Shanu; Lin Oscar; Chu Feixia; Patil Sujata; Erdjument-Bromage Hediye; Zanzonico Pat; Hudis Clifford; Studer Lorenz; Roboz Gail J.; Cesarman Ethel; Cerchietti Leandro; Levine Ross; Melnick Ari; Larson Steven M.; Lewis Jason S.; Guzman Monica L.; Chiosis Gabriela;

  • 作者单位

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, Lymphoma Serv, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Weill Cornell Med Coll, Dept Med, Haematol & Med Oncol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA|Rowan Univ, Dept Biol, Glassboro, NJ 08028 USA|Rowan Univ, Dept Biomed & Translat Sci, Glassboro, NJ 08028 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA;

    Tech Univ Cluj Napoca, Dept Math, Cluj Napoca 400114, Romania;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Univ New Hampshire, Mol Cellular & Biomed Sci, Durham, NH 03824 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, Breast Canc Serv, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA;

    Univ New Hampshire, Mol Cellular & Biomed Sci, Durham, NH 03824 USA;

    Mem Sloan Kettering Canc Ctr, Dept Epidemiol Biostat, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Program Mol Biol, Microchem & Prote Core, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, Breast Canc Serv, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA;

    Weill Cornell Med Coll, Dept Med, Haematol & Med Oncol, New York, NY 10065 USA;

    Weill Cornell Med Coll, Dept Med, Haematol & Med Oncol, New York, NY 10065 USA;

    Weill Cornell Med Coll, Dept Med, Haematol & Med Oncol, New York, NY 10065 USA;

    Sloan Kettering Inst, Human Oncol & Pathogenesis Program, New York, NY 10065 USA;

    Weill Cornell Med Coll, Dept Med, Haematol & Med Oncol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA;

    Weill Cornell Med Coll, Dept Med, Haematol & Med Oncol, New York, NY 10065 USA;

    Sloan Kettering Inst, Program Chem Biol, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, Breast Canc Serv, New York, NY 10065 USA;

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