KITAHARA Shuji    Department   Research Institutes and Facilities, Research Institutes and Facilities    Position   Associate Professor (Fixed Term)
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.
Journal	Formal name：Nature cell biology Abbreviation：Nat Cell Biol ISSN code：(1476-4679)1465-7392(Linking)
Domestic / Foregin	Foregin
Volume, Issue, Page	21(8),pp.1003-1014
Author and coauthor	Kofuji Satoshi, Hirayama Akiyoshi, Eberhardt Alexander Otto, Kawaguchi Risa, Sugiura Yuki, Sampetrean Oltea, Ikeda Yoshiki, Warren Mikako, Sakamoto Naoya, Kitahara Shuji, Yoshino Hirofumi, Yamashita Daisuke, Sumita Kazutaka, Wolfe Kara, Lange Lisa, Ikeda Satsuki, Shimada Hiroko, Minami Noriaki, Malhotra Akshiv, Morioka Shin, Ban Yuki, Asano Maya, Flanary Victoria L, Ramkissoon Annmarie, Chow Lionel M L, Kiyokawa Juri, Mashimo Tomoyuki, Lucey Greg, Mareninov Sergey, Ozawa Tatsuya, Onishi Nobuyuki, Okumura Koichi, Terakawa Jumpei, Daikoku Takiko, Wise-Draper Trisha, Majd Nazanin, Kofuji Kaori, Sasaki Mika, Mori Masaru, Kanemura Yonehiro, Smith Eric P, Anastasiou Dimitrios, Wakimoto Hiroaki, Holland Eric C, Yong William H, Horbinski Craig, Nakano Ichiro, DeBerardinis Ralph J, Bachoo Robert M, Mischel Paul S, Yasui Wataru, Suematsu Makoto, Saya Hideyuki, Soga Tomoyoshi, Grummt Ingrid, Bierhoff Holger, Sasaki Atsuo T
Publication date	2019/08
Summary	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.
DOI	10.1038/s41556-019-0363-9
PMID	31371825