TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and dynamic nuclear localization

• DOI: 10.4161/cc.23825
• Publication Date: 2013-03-13T16:07:37Z
• Authors: Jessica L. Bell; Alena Malyukova; Maria Kavallaris; Glenn M. Marshall; Belamy B. Cheung
• Keywords: 0301 basic medicine; TRIM16; EBBP; localization; Tripartite Motif Proteins; Mice; Neuroblastoma; Cell Movement; Cyclin D1; anzsrc-for: 31 Biological Sciences; RNA, Small Interfering; Cancer; Pediatric; Tumor; anzsrc-for: 111209 Solid Tumours; anzsrc-for: 3101 Biochemistry and Cell Biology; p27; Active Transport; DNA-Binding Proteins; anzsrc-for: 111201 Cancer Cell Biology; anzsrc-for: 0601 Biochemistry and Cell Biology; cell cycle; RNA Interference; Cyclin-Dependent Kinase Inhibitor p27; 570; Tyrosine 3-Monooxygenase; Pediatric Cancer; 1.1 Normal biological development and functioning; Ubiquitin-Protein Ligases; proliferation; Active Transport, Cell Nucleus; 610; 3101 Biochemistry and Cell Biology; Small Interfering; Cell Line; 03 medical and health sciences; Rare Diseases; Report; Cell Line, Tumor; Animals; Humans; Cell Proliferation; Cell Nucleus; anzsrc-for: 111403 Paediatrics; Neurosciences; G1 Phase; G1 Phase Cell Cycle Checkpoints; HEK293 Cells; RNA; 31 Biological Sciences; Transcription Factors

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.