The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress

被引：22

作者：

Zhang, Qi ^{[1
,2
]}

Zhou, Xiang ^{[1
,2
]}

Wu, RuiZhi ^{[1
,2
]}

Mosley, Amber ^{[3
]}

Zeng, Shelya X. ^{[1
,2
]}

Xing, Zhen ^{[4
]}

Lu, Hua ^{[1
,2
]}

机构：

[1] Tulane Univ, Sch Med, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA

[2] Tulane Univ, Sch Med, Tulane Canc Ctr, New Orleans, LA 70112 USA

[3] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

来源：

ELIFE | 2014年 / 3卷

关键词：

INOSINE MONOPHOSPHATE DEHYDROGENASE; MYCOPHENOLIC-ACID; CRYSTAL-STRUCTURE; CELL-LINES; P53; APOPTOSIS; COMPLEX; ACTIVATION; INHIBITORS; NUCLEOSTEMIN;

D O I：

10.7554/eLife.03077

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1 / 11

页数：11

共 42 条

[1] Sirtuin inhibitors [J].