Joshua T. Mendell

Joshua Mendell is one of the world's leading researchers on microRNA biology in cancer, whose work at UT Southwestern Medical Center and the Howard Hughes Medical Institute has defined how oncogenic transcription factors exploit microRNA networks to drive tumor initiation and progression, and conversely how p53 and other tumor suppressors deploy microRNAs as key effectors of their growth-suppressive programs. Mendell's most influential early contribution was the characterization of the miR-17-92 cluster — a polycistronic microRNA locus on chromosome 13q31 that he showed is directly transcriptionally activated by the MYC oncogene and functions as a potent oncomiR. MYC-driven miR-17-92 expression suppresses the expression of anti-proliferative and pro-apoptotic targets including E2F1 (through a feedback loop), PTEN, and BIM, creating a microRNA-mediated amplifier of oncogenic signaling. The miR-17-92 cluster is amplified in multiple human cancers including B-cell lymphoma, lung cancer, and colorectal cancer, and Mendell's demonstration of its MYC-driven oncogenic function provided one of the earliest mechanistic links between a transcription factor oncogene and miRNA-based gene regulatory networks. Equally significant is Mendell's characterization of the p53-microRNA axis. His laboratory demonstrated that p53 directly activates transcription of the miR-34 family (miR-34a, miR-34b/c), and that miR-34 family members are key effectors of p53 tumor suppressor function. miR-34a targets multiple pro-proliferative and anti-apoptotic mRNAs including CDK4, CDK6, MET, BCL2, and SIRT1, and constitutes a downstream arm of the p53 DNA damage response that enforces cell cycle arrest and apoptosis. Loss of miR-34 expression in cancers with TP53 mutation contributes to evasion of p53-dependent growth control. Mendell has also made fundamental contributions to understanding miRNA biogenesis regulation. His laboratory identified XRN2 as a nuclear exoribonuclease that degrades pre-miRNA hairpins that fail efficient Drosha processing, quality-controlling the miRNA processing pipeline. He characterized how the RNA helicase DDX5 and multiple co-factors modulate Drosha processivity on specific primary miRNA substrates, adding a new layer of regulation to the miRNA biogenesis pathway. More recently, Mendell's laboratory has defined the role of nonsense-mediated decay (NMD) in cancer, identifying recurrent NMD pathway mutations in human tumors and showing how NMD suppression stabilizes oncogenic transcripts and contributes to cancer hallmarks.

Joshua Mendell 是癌症 microRNA 生物学领域的世界顶尖研究者，他的工作定义了癌基因转录因子如何利用 microRNA 网络驱动肿瘤发生，以及 p53 等肿瘤抑制因子如何将 microRNA 作为抑制生长程序的关键效应因子。 他最具影响力的早期贡献是表征 miR-17-92 簇——他证明该多顺反子 miRNA 基因座由 MYC 癌基因直接转录激活，并通过抑制 E2F1（形成反馈环）、PTEN 和 BIM 等抗增殖靶标发挥强效癌促 miRNA 功能。同样重要的是他对 p53-microRNA 轴的表征：他证明 p53 直接激活 miR-34 家族（miR-34a、miR-34b/c）的转录，miR-34 成员通过靶向 CDK4、CDK6、MET、BCL2 和 SIRT1 构成 p53 肿瘤抑制功能的关键下游效应臂。