title: TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and dynamic nuclear localization.
abstract: Neuroblastoma is the most common solid tumor in childhood and represents 15% of all children's cancer deaths. We have previously demonstrated that tripartite motif 16 (TRIM16), a member of the RING B-box coiled-coil (RBCC)/tripartite totif (TRIM) protein family, has significant effects on neuroblastoma proliferation and migration in vitro and tumorigenicity in vivo. However, the mechanism by which this putative tumor suppressor influences cell proliferation and tumorigenicity was undetermined. Here we show, for the first time, TRIM16's striking pattern of expression and dynamic localization during cell cycle progression and neuroblastoma tumor development. In a tyrosine hydroxylase MYCN (TH-MYCN) neuroblastoma mouse model, immunohistochemical staining revealed strong nuclear TRIM16 expression in differentiating ganglia cells but not in the tumor-initiating cells. Furthermore in vitro studies clearly demonstrated that during G 1 cell cycle phase, TRIM16 protein expression is upregulated and shifts to the nucleus of cells. TRIM16 also plays a role in cell cycle progression through changes in Cyclin D1 and p27 expression. Importantly, using TRIM16 deletion mutants, an uncharacterized protein domain of TRIM16 was found to be required for both TRIM16's growth inhibitory effects and its nuclear localization. Taken together, our data suggest that TRIM16 acts as a novel regulator of both neuroblastoma G 1/S progression and cell differentiation.
authors: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW Australia.
authors: Jessica L
authors: JL
authors: Bell
authors: Alena
authors: A
authors: Malyukova
authors: Maria
authors: M
authors: Kavallaris
authors: Glenn M
authors: GM
authors: Marshall
authors: Belamy B
authors: BB
authors: Cheung
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D059585:G1 Phase Cell Cycle Checkpoints; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014446:Tyrosine 3-Monooxygenase; C117731:TRIM16 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: EBBP; TRIM16; cancer; cell cycle; cyclin D1; localization; neuroblastoma; p27; proliferation