Functional Interactions between BM88/Cend1, Ran-Binding Protein M and Dyrk1B Kinase Affect Cyclin D1 Levels and Cell Cycle Progression/Exit in Mouse Neuroblastoma Cells

Abstract

BM88/Cend1 is a neuronal-lineage specific modulator with a pivotal role in coordination of cell cycle exit and differentiation of neuronal precursors. In the current study we identified the signal transduction scaffolding protein Ran-binding protein M (RanBPM) as a BM88/Cend1 binding partner and showed that BM88/Cend1, RanBPM and the dual specificity tyrosine-phosphorylation regulated kinase 1B (Dyrk1B) are expressed in mouse brain as well as in cultured embryonic cortical neurons while RanBPM can form complexes with either of the two other proteins. To elucidate a potential mechanism involving BM88/Cend1, RanBPM and Dyrk1B in cell cycle progression/exit, we transiently co-expressed these proteins in mouse neuroblastoma Neuro 2a cells. We found that the BM88/Cend1-dependent or Dyrk1B-dependent down-regulation of cyclin D1 is reversed following their functional interaction with RanBPM. More specifically, functional interaction of RanBPM with either BM88/Cend1 or Dyrk1B stabilizes cyclin D1 in the nucleus and promotes 5-bromo-2'-deoxyuridine (BrdU) incorporation as a measure of enhanced cell proliferation. However, the RanBPM-dependent Dyrk1B cytosolic retention and degradation is reverted in the presence of Cend1 resulting in cyclin D1 destabilization. Co-expression of RanBPM with either BM88/Cend1 or Dyrk1B also had a negative effect on Neuro 2a cell differentiation. Our results suggest that functional interactions between BM88/Cend1, RanBPM and Dyrk1B affect the balance between cellular proliferation and differentiation in Neuro 2a cells and indicate that a potentially similar mechanism may influence cell cycle progression/exit and differentiation of neuronal precursors.

Isatin inhibits the proliferation and invasion of SH-SY5Y neuroblastoma cells

“…Cyclin D1 is one of the key regulatory proteins for the G 1 -S transition of the cell cycle. Overexpression of cyclin D1 has been found in numerous types of solid tumor, including neuroblastoma, bladder cancer, prostate cancer and breast cancer (20)(21)(22)(23). The results of the present study suggested that isatin causes G 1 -phase arrest and inhibits the proliferation of SH-SY5Y cells by downregulating cyclin D1 expression.…”

LY75 Ablation Mediates Mesenchymal-Epithelial Transition (MET) in Epithelial Ovarian Cancer (EOC) Cells Associated with DNA Methylation Alterations and Suppression of the Wnt/β-Catenin Pathway

“…CEND1 (cell cycle exit and neuronal differentiation protein 1) plays an important role in neuronal differentiation by modulating cell cycle progression/exit or apoptosis of neuronal progenitors [79]. CEND1 was shown to suppress cell proliferation via modulating the cyclin D1 pathway, which is linked to its potential tumor suppressor functions, associated with proliferation inhibition of neuroblastoma cells [80]. CEND1 was found to be epigenetically suppressed by methylation in invasive breast carcinoma, also suggestive for a potential tumor suppressor role in this cancer type [81].…”

Novel Significant Stage-Specific Differentially Expressed Genes in Liver Hepatocellular Carcinoma

“…PECAM1 overexpression has been linked to peritoneal recurrence of stage II/III gastric cancer patients (Terashima et al, 2017). CEND1 has been identified as a cell-cycle protein (Tsioras et al, 2013). PGAM2 is a glycolytic enzyme whose upregulation is essential for tumor cell proliferation (Xu et al, 2014).…”