Journal Article

DKFZ-2019-01982

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

Kofuji, S. ; Hirayama, A. ; Eberhardt, A. O. ; Kawaguchi, R. ; Sugiura, Y. ; Sampetrean, O. ; Ikeda, Y. ; Warren, M. ; Sakamoto, N. ; Kitahara, S. ; Yoshino, H. ; Yamashita, D. ; Sumita, K. ; Wolfe, K. ; Lange, L. ; Ikeda, S. ; Shimada, H. ; Minami, N. ; Malhotra, A. ; Morioka, S. ; Ban, Y. ; Asano, M. ; Flanary, V. L. ; Ramkissoon, A. ; Chow, L. M. L. ; Kiyokawa, J. ; Mashimo, T. ; Lucey, G. ; Mareninov, S. ; Ozawa, T. ; Onishi, N. ; Okumura, K. ; Terakawa, J. ; Daikoku, T. ; Wise-Draper, T. ; Majd, N. ; Kofuji, K. ; Sasaki, M. ; Mori, M. ; Kanemura, Y. ; Smith, E. P. ; Anastasiou, D. ; Wakimoto, H. ; Holland, E. C. ; Yong, W. H. ; Horbinski, C. ; Nakano, I. ; DeBerardinis, R. J. ; Bachoo, R. M. ; Mischel, P. S. ; Yasui, W. ; Suematsu, M. ; Saya, H. ; Soga, T. ; Grummt, I.DKFZ* ; Bierhoff, H. ; Sasaki, A. T.

2019
Nature America New York, NY

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Please use a persistent id in citations: doi:10.1038/s41556-019-0363-9

Abstract: In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

Note: DKFZ-ZMBH Alliance

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Contributing Institute(s):

1. Molekularbiologie der Zelle II (A030)

Research Program(s):

1. 311 - Signalling pathways, cell and tumor biology (POF3-311) (POF3-311)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 15 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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