BM88 Is a Dual Function Molecule Inducing Cell Cycle Exit and Neuronal Differentiation of Neuroblastoma Cells via Cyclin D1 Down-regulation and Retinoblastoma Protein Hypophosphorylation

Abstract

Control of cell cycle progression/exit and differentiation of neuronal precursors is of paramount importance during brain development. BM88 is a neuronal protein associated with terminal neuron-generating divisions in vivoThe formation of the nervous system is governed by a delicate balance between cell proliferation, subsequent cell cycle withdrawal, and differentiation to distinctive neuronal phenotypes (1, 2). Current observations have highlighted the existence of mechanisms coupling cell cycle exit and differentiation as well as functional cross-talk between intrinsic factors controlling these two mechanisms. A number of key factors regulating cell cycle progression have been implicated in cell fate determination and differentiation of neuronal precursors, whereas specification-and/or differentiation-inducing molecules are beginning to emerge as cell cycle regulators (3-6). However, there are still important questions regarding the timing control of the proliferation/differentiation switch that remain unanswered.In the central nervous system, control of cell cycle progression plays an essential role in the generation of the appropriate number of neurons and the formation of functional neuronal circuits. When a neuronal progenitor is committed to undergo differentiation, it exits from the G 1 phase of the cell cycle and enters into an irreversible quiescent state referred to as G 0 . The tumor suppressor proteins p53 and pRb 6 are central regulators of this progression (7). p53, when activated, causes G 1 arrest at the G 0 restriction point by inducing expression of p21 and consequent inhibition of D-type cyclins and related cyclin-dependent kinases (8 -10), thus preventing phosphorylation of pRb (7). Under these conditions, hypophosphorylated pRb associates with the E2F family of transcription factors, thus impairing their ability to transactivate genes required for cell cycle progression (11). As a consequence cells do not progress through the G 1 -to-S phase transition. Several studies have indicated that a critical event associated with cell cycle withdrawal and differentiation both in neuronal and non-neuronal cells is the cellular compartmentalization of cyclin D1, which shifts from a predominantly nuclear localization to cytoplasmic sequestration

BM88/CEND1 coordinates cell cycle exit and differentiation of neuronal precursors

“…Here, we demonstrated that BM88 is necessary for proper regulation of proliferation and neuronal differentiation of NPCs derived from embryonic mouse spinal cord. In agreement, we have recently reported that BM88 knockdown in a neuroblastoma cell line enhanced proliferation and impaired retinoic acid-induced neuronal differentiation (11). Collectively, these data implicate BM88 in synchronization of cell cycle exit and neuronal lineage progression.…”

“…Thus, although its effect on cell cycle exit is similar along the dorsoventral axis of the neural tube, the effect on neuron generation is more successfully terminated in the ventral spinal cord within the MN domain. A similar context-dependent requirement for the neurogenic potential of BM88 was noted in vitro (11). Thus, BM88 induces neurogenesis in neural cells possessing the appropriate machinery for neuronal differentiation, whereas it seems to direct nonneural cells toward cell cycle exit and, eventually, to a proapoptotic pathway.…”

“…This raised the question of how this function is achieved. Recently reported data suggest that BM88 promotes cell cycle exit through the p53/cyclin D1/pRb signaling pathway (11). In neuroblastoma cells, BM88 is sufficient to induce up-regulation and nuclear accumulation of p53, as well as activation of its downstream mediator p21 WAF/Cip1 and dephosphorylation of pRb, known to be responsible for growth arrest and G 1 accumulation of neuronal and nonneuronal cells in response to growth arrest signals (21).…”

“…This intimate correlation between BM88 expression and the progression of progenitor cells toward neuronal differentiation suggested that BM88 may be functionally involved in this process. In support, we have recently shown (11) that BM88 is sufficient and necessary for accomplishment of cell cycle exit and differentiation of mouse neuroblastoma cells toward a neuronal phenotype via (i) activation of the p53-pRb signaling pathway that controls the balance between cell cycle progression and exit and (ii) cyclin D1 down-regulation and cytoplasmic sequestration, which is a key event for progenitor cell survival and differentiation into postmitotic neurons (12).…”

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

“…Our data have shown that loss of Hap1 can lead to enhanced interaction between Dcaf7 and DYRK1A, resulting in an increase in DYRK1A. It has been reported that increased DYRK1A can affect cell-cycle regulation and neuronal differentiation by reducing cyclin D1 and the cyclindependent kinase inhibitor p21 (49,50), two important proteins that promote neuronal differentiation (50)(51)(52)(53)(54). Thus, we isolated hypothalamic tissues from WT and Hap1-KO postnatal pups and performed Western blotting with anti-cyclin D1 and anti-p21.…”