Cremona Catherine A, Sancho Rocio, Diefenbacher Markus E, Behrens Axel
The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Semin Cancer Biol. 2016 Feb;36:52-61. doi: 10.1016/j.semcancer.2015.09.006. Epub 2015 Sep 26.
Fbw7 is well characterised as a stem cell regulator and tumour suppressor, powerfully positioned to control proliferation, differentiation and apoptosis by targeting key transcription factors for ubiquitination and destruction. Evidence in support of these roles continues to accumulate from in vitro studies, mouse models and human patient data. Here we summarise the latest of these findings, highlighting the tumour-suppressive role of Fbw7 in multiple tissues, and the rare circumstances where Fbw7 activity can be oncogenic. We discuss mechanisms that regulate ubiquitination by Fbw7, including ubiquitin-specific proteases such as USP28 that counteract Fbw7 activity and thereby stabilise oncoproteins. Deubiquitination of key Fbw7 substrates to prevent their destruction is beginning to be appreciated as an important pro-tumourigenic mechanism. As the ubiquitin-proteasome system represents a largely untapped field for drug development, the interplay between Fbw7 and its counterpart deubiquitinating enzymes in tumours is likely to attract increasing interest and influence future treatment strategies.
Fbw7作为一种干细胞调节因子和肿瘤抑制因子已被充分表征，它通过靶向关键转录因子进行泛素化和降解，在控制细胞增殖、分化和凋亡方面具有强大作用。来自体外研究、小鼠模型和人类患者数据的证据不断积累，支持这些作用。在此，我们总结这些最新发现，强调Fbw7在多种组织中的肿瘤抑制作用，以及Fbw7活性可能具有致癌性的罕见情况。我们讨论了Fbw7调节泛素化的机制，包括泛素特异性蛋白酶（如USP28），它们可抵消Fbw7的活性，从而稳定癌蛋白。关键Fbw7底物的去泛素化以防止其被破坏，正开始被视为一种重要的促肿瘤发生机制。由于泛素-蛋白酶体系统在很大程度上仍是药物开发的未开发领域，Fbw7与其对应的去泛素化酶在肿瘤中的相互作用可能会引起越来越多的关注，并影响未来的治疗策略。
