The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress.
The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress.
复制标题
作者：
Zhang Q;Zhou X;Wu R;Mosley A;Zeng SX;Xing Z;Lu H
“核糖体应激(RS)-p53通路”是由干扰核糖体生物发生的任何应激源或遗传改变触发的，并由几种核糖体蛋白（RPs）介导，如RPL11和RPL5，它们抑制MDM2并激活p53。肌苷单磷酸（IMP）脱氢酶2 （IMPDH2）是一种新的鸟嘌呤核苷酸生物合成的限速酶，对于维持DNA和RNA合成所需的细胞鸟嘌呤脱氧和核糖核苷酸库至关重要。它在许多恶性肿瘤中高度表达。我们之前的研究表明，抑制IMPDH2通过引起RS导致p53激活。令人惊讶的是，我们目前的研究表明，INZ (INZ)，一种新型的非基因毒性p53激活剂，通过抑制SIRT1，也可以抑制细胞IMPDH2活性，降低细胞GTP和GTP结合核干蛋白的水平，这是rRNA加工所必需的。因此，INZ诱导RS和RPL11/RPL5-MDM2相互作用，激活p53。这些结果支持了INZ通过双重靶向SIRT1和IMPDH2来抑制癌细胞生长的新观点。当细胞失去控制自身生长的能力时，癌症就会发生。大约一半的癌性肿瘤携带一种叫做p53的蛋白质的功能失调版本，而另一半则在对p53的产生和功能很重要的蛋白质上有缺陷。当一个健康细胞暴露于有害的化学物质或试剂中时，p53蛋白会触发旨在修复损伤的反应。然而，如果这些尝试失败，p53会导致受损细胞自我毁灭。由于p53控制过程中的缺陷导致细胞不受限制地生长并可能导致癌症，因此它是一个非常有吸引力的癌症治疗靶点。癌症药物的发展主要集中在直接靶向p53和靶向与p53一起工作的蛋白质上。两种叫做Mdm2和SIRT1的蛋白质特别令人感兴趣。Mdm2结合，失活，并导致p53的降解。SIRT1可以修饰p53，使其更容易被Mdm2接近，并且在癌细胞中经常发现非常高的水平。2012年，研究人员发现Inauhzin是一种小分子，可能用于治疗仍然具有p53蛋白功能版本的肿瘤。Inauhzin被认为是通过抑制SIRT1来起作用的，SIRT1会增加p53的水平——可能是通过它对Mdm2的作用。这可以恢复细胞控制其生长的能力，如果它受到不可修复的损伤，就会死亡。然而，并不是所有这种小分子对细胞的影响都可以用它与SIRT1的相互作用来解释。现在Zhang等人，包括参与2012年工作的一些研究人员，已经研究了Inauhzin是否也与细胞中的其他蛋白质相互作用；发现Inauhzin与一种叫做IMPDH2的酶结合。这种酶参与制造gtp——一种参与活细胞许多重要过程的小分子。Zhang等人证明Inauhzin对IMPDH酶的作用引发了一种不涉及SIRT1蛋白的反应，最终导致Mdm2活性降低，p53活性恢复。癌症治疗通常包括针对不同蛋白质的药物组合，目的是减少肿瘤对治疗产生抗药性的可能性。Inauhzin对两种不同的蛋白质的作用，导致p53的激活，不仅增加了它的效力，而且降低了产生耐药性的可能性。DOI: http://dx.doi.org/10.7554/eLife.03077.002
The ‘ribosomal stress (RS)-p53 pathway’ is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. Inosine monophosphate (IMP) dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2. DOI: http://dx.doi.org/10.7554/eLife.03077.001 Cancer develops when cells lose the ability to control their own growth. About half of cancerous tumors carry a dysfunctional version of a protein called p53, while the other half have defects in proteins that are important for p53's production and function. When a healthy cell is exposed to damaging chemicals or agents, the p53 protein triggers responses that are aimed at repairing the damage. However, if these attempts fail, p53 causes the damaged cell to essentially destroy itself. As defects in p53-controlled processes cause cells to grow unrestrictedly and can lead to cancer, it is a very attractive target for cancer therapies. Cancer drug developments have focused on both targeting p53 directly and targeting the proteins that work with p53. Two proteins called Mdm2 and SIRT1 are of particular interest. Mdm2 binds to, inactivates, and leads to the degradation of p53. SIRT1 can modify p53 and make it more accessible to Mdm2, and is often found in very high levels in cancer cells. In 2012, researchers identified Inauhzin as a small molecule that could potentially be used to treat tumors that still have a functional version of the p53 protein. Inauhzin was thought to work by inhibiting SIRT1, which increases p53 levels—probably through its effects on Mdm2. This restores the cell's ability to control its growth and to die if it is irreparably damaged. However, not all of this small molecule's effects on cells can be explained by its interaction with SIRT1. Now Zhang et al., including some of the researchers involved in the 2012 work, have investigated whether Inauhzin also interacts with other proteins in the cell; and Inauhzin was revealed to bind an enzyme called IMPDH2. This enzyme is involved in making GTP—a small molecule that is involved in many important processes in living cells. Zhang et al. demonstrated that Inauhzin's effect on the IMPDH enzyme triggered a response that did not involve the SIRT1 protein, and that ultimately led to a decrease in Mdm2 activity and restored p53 activity. Cancer treatments often include a combination of drugs that target different proteins with the goal of reducing the likelihood of a tumor becoming resistant to the treatment. Inauhzin's effect on two different proteins that lead to p53 activation not only increases its potency, but also makes it less likely that drug resistance will develop. DOI: http://dx.doi.org/10.7554/eLife.03077.002