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TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and dynamic nuclear localization
Jessica L Bell1, Alena Malyukova, Maria Kavallaris
1Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW Australia.
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.
Insights
Tripartite motif 16 (TRIM16) is a tumor suppressor impacting neuroblastoma growth. TRIM16 regulates cell cycle progression and nuclear localization, suggesting a novel role in controlling neuroblastoma development.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Neuroblastoma is a common childhood cancer with significant mortality.
- Tripartite motif 16 (TRIM16) has shown effects on neuroblastoma proliferation, migration, and tumorigenicity.
- The precise mechanism of TRIM16's tumor suppressor function in neuroblastoma remained unclear.
Purpose of the Study:
- To elucidate the mechanism of TRIM16's role in neuroblastoma proliferation and tumorigenicity.
- To investigate TRIM16's expression pattern and localization during cell cycle and tumor development.
- To identify specific TRIM16 domains responsible for its biological functions.
Main Methods:
- Immunohistochemical staining in a TH-MYCN neuroblastoma mouse model.
- In vitro studies on cell cycle progression and protein expression.
- Analysis of TRIM16 deletion mutants to assess domain function.
Main Results:
- TRIM16 exhibits distinct expression patterns in neuroblastoma, with nuclear localization in differentiating cells but not tumor-initiating cells.
- TRIM16 expression is upregulated and shifts to the nucleus during the G1 phase of the cell cycle.
- TRIM16 influences cell cycle regulators Cyclin D1 and p27, and an uncharacterized domain is crucial for its growth inhibitory effects and nuclear localization.
Conclusions:
- TRIM16 acts as a novel regulator of neuroblastoma cell cycle progression (G1/S phase).
- TRIM16 plays a role in promoting neuroblastoma cell differentiation.
- TRIM16's nuclear localization and specific protein domains are critical for its tumor-suppressive functions.
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