title: Maintenance of tumor initiating cells of defined genetic composition by nucleostemin.
abstract: Recent work has identified a subset of cells resident in tumors that exhibit properties similar to those found in normal stem cells. Such cells are highly tumorigenic and may be involved in resistance to treatment. However, the genes that regulate the tumor initiating cell (TIC) state are unknown. Here, we show that overexpression of either of the nucleolar GTP-binding proteins nucleostemin (NS) or GNL3L drives the fraction of genetically defined tumor cells that exhibit markers and tumorigenic properties of TICs. Specifically, cells that constitutively express elevated levels of NS or GNL3L exhibit increased TWIST expression, phosphorylation of STAT3, expression of genes that induce pluripotent stem cells, and enhanced radioresistance; in addition, they form tumors even when small numbers of cells are implanted and exhibit an increased propensity to metastasize. GNL3L/NS forms a complex with the telomerase catalytic subunit [human telomerase reverse transcriptase (hTERT)] and the SWItch-Sucrose NonFermentable (SWI-SNF) complex protein brahma-related gene 1 (BRG1), and the expression of each of these components is necessary to facilitate the cancer stem cell state. Together, these observations define a complex composed of TERT, BRG1, and NS/GNL3L that maintains the function of TICs.
authors: Division of Cancer Stem Cell,  National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045,  Japan.
authors: Naoko
authors: N
authors: Okamoto
authors: Mami
authors: M
authors: Yasukawa
authors: Christine
authors: C
authors: Nguyen
authors: Vivi
authors: V
authors: Kasim
authors: Yoshiko
authors: Y
authors: Maida
authors: Richard
authors: R
authors: Possemato
authors: Tatsuhiro
authors: T
authors: Shibata
authors: Keith L
authors: KL
authors: Ligon
authors: Kiyoko
authors: K
authors: Fukami
authors: William C
authors: WC
authors: Hahn
authors: Kenkichi
authors: K
authors: Masutomi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry*; D002466:Cell Nucleolus / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C469949:GNL3 protein, human; C509155:GNL3L protein, human; C524643:GNL3L protein, mouse; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; C470311:nucleostemin protein, mouse; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse; D019204:GTP-Binding Proteins; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse; D004265:DNA Helicases