It's Getting Complicated-A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy.
It's Getting Complicated-A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy.
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DOI：
10.3389/fcell.2022.818744
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发表时间：
2022
影响因子：
5.5
通讯作者：
Weber JD
中科院分区：
文献类型：
--
作者：
Kung CP;Weber JD
在致癌压力下，由肿瘤抑制因子 p53 介导的抗肿瘤机制是我们身体对抗癌症发生和发展的最强大武器。因此，具有显着 p53 调节活性的因子一直是癌症研究界非常感兴趣的主题。其中，MDM2 和 ARF 因其分别抑制和激活 p53 功能的能力而被认为是最有影响力的 p53 调节因子。 MDM2 通过促进 p53 的泛素化和蛋白酶体介导的降解来抑制 p53，而 ARF 通过与 MDM2 发生物理相互作用以阻止其接触 p53 来激活 p53。这种对 p53-MDM2-ARF 功能三角的传统理解指导了 p53 研究的方向，以及过去 30 年基于 p53 的治疗策略的发展。在此期间，我们对这个三角关系的了解不断增加，特别是通过鉴定 MDM2 和 ARF 的 p53 独立功能，发现了许多连接这三种蛋白质的未被充分认识的分子机制。通过认识它们之间的拮抗和协同关系，我们对利用这些关系来开发有效的癌症疗法的考虑需要相应地更新。在这篇综述中，我们将重新审视有关 p53-MDM2-ARF 肿瘤调节机制的传统观点，重点介绍有助于现代认识其关系的有影响力的研究，并总结针对这一途径进行有效癌症治疗的持续努力。对 p53-MDM2-ARF 网络的全新认识可以带来创新方法来开发新一代遗传信息和临床有效的癌症疗法。
Anti-tumorigenic mechanisms mediated by the tumor suppressor p53, upon oncogenic stresses, are our bodies’ greatest weapons to battle against cancer onset and development. Consequently, factors that possess significant p53-regulating activities have been subjects of serious interest from the cancer research community. Among them, MDM2 and ARF are considered the most influential p53 regulators due to their abilities to inhibit and activate p53 functions, respectively. MDM2 inhibits p53 by promoting ubiquitination and proteasome-mediated degradation of p53, while ARF activates p53 by physically interacting with MDM2 to block its access to p53. This conventional understanding of p53-MDM2-ARF functional triangle have guided the direction of p53 research, as well as the development of p53-based therapeutic strategies for the last 30 years. Our increasing knowledge of this triangle during this time, especially through identification of p53-independent functions of MDM2 and ARF, have uncovered many under-appreciated molecular mechanisms connecting these three proteins. Through recognizing both antagonizing and synergizing relationships among them, our consideration for harnessing these relationships to develop effective cancer therapies needs an update accordingly. In this review, we will re-visit the conventional wisdom regarding p53-MDM2-ARF tumor-regulating mechanisms, highlight impactful studies contributing to the modern look of their relationships, and summarize ongoing efforts to target this pathway for effective cancer treatments. A refreshed appreciation of p53-MDM2-ARF network can bring innovative approaches to develop new generations of genetically-informed and clinically-effective cancer therapies.
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影响因子：
5.7
作者：
Saito K;Iioka H;Kojima C;Ogawa M;Kondo E
通讯作者：
Kondo E
MDM2/X 靶向治疗的临床概述。
影响因子：
4.7
作者：
Burgess A;Chia KM;Haupt S;Thomas D;Haupt Y;Lim E
通讯作者：
Lim E
影响因子：
8
作者：
Ayrault, O;Andrique, L;Seite, P
通讯作者：
Seite, P
影响因子：
5.3
作者：
Apicelli, Anthony J.;Maggi, Leonard B., Jr.;Weber, Jason D.
通讯作者：
Weber, Jason D.
DOI：
10.1007/bf01535205
发表时间：
1987-05-01
期刊：
SOMATIC CELL AND MOLECULAR GENETICS
影响因子：
--
作者：
CAHILLYSNYDER, L;YANGFENG, T;GEORGE, DL
通讯作者：
GEORGE, DL