Zhang Qi, Zhou Xiang, Wu RuiZhi, Mosley Amber, Zeng Shelya X, Xing Zhen, Lu Hua
Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States.
Elife. 2014 Oct 27;3:e03077. doi: 10.7554/eLife.03077.
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.
“核糖体应激（RS）-p53通路”由任何破坏核糖体生物合成的应激源或基因改变触发，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）是从头合成鸟嘌呤核苷酸的限速酶，对维持DNA和RNA合成所需的细胞鸟嘌呤脱氧核苷酸和核糖核苷酸池至关重要。它在许多恶性肿瘤中高表达。我们之前表明，抑制IMPDH2会通过引起RS导致p53激活。令人惊讶的是，我们目前的研究表明，Inauzhin（INZ）作为一种通过抑制SIRT1的新型非基因毒性p53激活剂，也能抑制细胞IMPDH2活性，并降低细胞GTP和对rRNA加工至关重要的GTP结合核仁素水平。因此，INZ诱导RS以及RPL11/RPL5-MDM2相互作用，激活p53。这些结果支持了一个新观点，即INZ通过双重靶向SIRT1和IMPDH2来抑制癌细胞生长。
