Grieb Brian C, Eischen Christine M
Vanderbilt-Ingram Cancer Center, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Biology (Basel). 2022 Jun 8;11(6):881. doi: 10.3390/biology11060881.
The oncogenic transcription factor c-MYC (MYC) is highly conserved across species and is frequently overexpressed or dysregulated in human cancers. MYC regulates a wide range of critical cellular and oncogenic activities including proliferation, metabolism, metastasis, apoptosis, and differentiation by transcriptionally activating or repressing the expression of a large number of genes. This activity of MYC is not carried out in isolation, instead relying on its association with a myriad of protein cofactors. We determined that MDM Two Binding Protein (MTBP) indirectly binds MYC and is a novel MYC transcriptional cofactor. MTBP promotes MYC-mediated transcriptional activity, proliferation, and cellular transformation by binding in a protein complex with MYC at MYC-bound promoters. This discovery provided critical context for data linking MTBP to aging as well as a rapidly expanding body of evidence demonstrating MTBP is overexpressed in many human malignancies, is often linked to poor patient outcomes, and is necessary for cancer cell survival. As such, MTBP represents a novel and potentially broad reaching oncologic drug target, particularly when MYC is dysregulated. Here we have reviewed the discovery of MTBP and the initial controversy with its function as well as its associations with proliferation, MYC, DNA replication, aging, and human cancer.
致癌转录因子c-MYC（MYC）在物种间高度保守，在人类癌症中经常过度表达或失调。MYC通过转录激活或抑制大量基因的表达来调节广泛的关键细胞和致癌活动，包括增殖、代谢、转移、凋亡和分化。MYC的这种活动并非孤立进行，而是依赖于它与无数蛋白质辅因子的结合。我们确定MDM双结合蛋白（MTBP）间接结合MYC，是一种新型的MYC转录辅因子。MTBP通过在与MYC结合的启动子处与MYC形成蛋白复合物来促进MYC介导的转录活性、增殖和细胞转化。这一发现为将MTBP与衰老联系起来的数据提供了关键背景，也为越来越多的证据提供了背景，这些证据表明MTBP在许多人类恶性肿瘤中过度表达，常常与患者预后不良相关，并且是癌细胞存活所必需的。因此，MTBP代表了一种新型的、可能具有广泛影响的肿瘤药物靶点，特别是在MYC失调的情况下。在这里，我们回顾了MTBP的发现及其功能最初的争议，以及它与增殖、MYC、DNA复制、衰老和人类癌症的关联。
