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

Qi Zhang, Xiang Zhou, RuiZhi Wu, Amber Mosley, Shelya X. Zeng, Zhen Xing, Hua Lu

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere03077
Pages (from-to)1-11
Number of pages11
JournaleLife
Volume3
Issue numberOctober2014
DOIs
StatePublished - Oct 1 2014

Fingerprint

IMP Dehydrogenase
Inosine Monophosphate
Oxidoreductases
Guanosine Triphosphate
Ribonucleotides
Guanine Nucleotides
Ribosomal Proteins
Biosynthesis
Guanine
Cell growth
Neoplasms
Chemical activation
RNA
DNA
Enzymes
Growth
Processing
10-(2-(5H-(1,2,4)triazino(5,6-b)indol-3-ylthio)butanoyl)-10H-phenothiazine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Zhang, Q., Zhou, X., Wu, R., Mosley, A., Zeng, S. X., Xing, Z., & Lu, H. (2014). The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress. eLife, 3(October2014), 1-11. [e03077]. https://doi.org/10.7554/eLife.03077

The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress. / Zhang, Qi; Zhou, Xiang; Wu, RuiZhi; Mosley, Amber; Zeng, Shelya X.; Xing, Zhen; Lu, Hua.

In: eLife, Vol. 3, No. October2014, e03077, 01.10.2014, p. 1-11.

Research output: Contribution to journalArticle

Zhang, Q, Zhou, X, Wu, R, Mosley, A, Zeng, SX, Xing, Z & Lu, H 2014, 'The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress', eLife, vol. 3, no. October2014, e03077, pp. 1-11. https://doi.org/10.7554/eLife.03077
Zhang Q, Zhou X, Wu R, Mosley A, Zeng SX, Xing Z et al. The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress. eLife. 2014 Oct 1;3(October2014):1-11. e03077. https://doi.org/10.7554/eLife.03077
Zhang, Qi ; Zhou, Xiang ; Wu, RuiZhi ; Mosley, Amber ; Zeng, Shelya X. ; Xing, Zhen ; Lu, Hua. / The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress. In: eLife. 2014 ; Vol. 3, No. October2014. pp. 1-11.
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