Coordination of cell cycle exit and differentiation of neuronal progenitors

Politis, Panagiotis K.; Thomaidou, Dimitra; Matsas, Rebecca

doi:10.4161/cc.7.6.5550

Cited by 39 publications

(33 citation statements)

References 98 publications

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“…Decelerated cell cycle progression is often linked to the commitment of cell fate determination (11,12,(33)(34)(35). Previously, cell cycle proteins of pluripotent cells were thought to control only the escape from the terminal cell cycle during differentiation, although their levels always remain in a state of flux.…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, the members of the let-7 family are among the most abundant miRNAs in adult brain. Such cell fate determination is a complex process and needs to be precisely coordinated with exit from cell cycle (11,12), and therefore involves crosstalk between the molecular pathways controlling proliferation and differentiation. Because let-7 miRNAs are tightly governed by Lin28a in neural stem cells, a prompt mechanism is required to respond to environmental signal and attenuate the inhibitory effect of Lin28a.…”

Section: Edited By Roger J Colbranmentioning

confidence: 99%

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Extracellular Signal-regulated Kinases (ERKs) Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation

Lei

Chen

et al. 2017

Journal of Biological Chemistry

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Edited by Roger J. ColbranLin28a, originally discovered in the nematode Caenorhabditis elegans and highly conserved across species, is a well characterized regulator of let-7 microRNA (miRNA) and is implicated in cell proliferation and pluripotency control. However, little is known about how Lin28a function is modulated at the posttranslational level and thereby responds to major signaling pathways. Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200. By editing lin28a gene with the CRISPR/Cas9-based method, we generated P19 mouse embryonic carcinoma stem cells expressing Lin28a-S200A (phosphodeficient) and Lin28a-S200D (phospho-mimetic) mutants, respectively, to study the functional impact of Ser-200 phosphorylation. Lin28a-S200D-expressing cells, but not Lin28a-S200A-expressing or control P19 embryonic carcinoma cells, displayed impaired inhibition of let-7 miRNA and resulted in decreased cyclin D1, whereas Lin28a-S200A knock-in cells expressed less let-7 miRNA, proliferated faster, and exhibited differentiation defect upon retinoic acid induction. Therefore our results support that ERK kinase-mediated Lin28a phosphorylation may be an important mechanism for pluripotent cells to facilitate the escape from the self-renewal cycle and start the differentiation process.Lin28a (cell lineage abnormal 28), an RNA-binding protein highly conserved across eukaryotes from Caenorhabditis elegans to mammals, is an important regulator involved in various physiological processes including cell proliferation, differentiation, and organism development, as well as metabolism homeostasis (1, 2). By directly binding to its target RNAs, Lin28a is known to inhibit maturation of let-7 miRNA 2 family and promotes their turnover (3, 4), thereby influencing an army of let-7 targets including c-Myc, Ras, and cyclin D1, as well as Lin28a itself (5, 6), which are master regulators of cell proliferation and the pluripotent status of stem cells. Although Lin28a is also found directly bound to mRNAs of several important metabolic enzymes and influences the translation of these mRNAs (6 -8), its function in stem cell differentiation and development is primarily dependent on let-7 miRNAs (3).The Lin28a-let-7 axis has been implicated in neurogenesis. Briefly, during the development of the central neural system, let-7 miRNAs quickly accumulate, and then silence target genes including pluripotency factors and fetal oncoproteins to drive the neural stem cells to differentiate (9, 10). As a consequence, the members of the let-7 family are among the most abundant miRNAs in adult brain. Such cell fate determination is a complex process and needs to be precisely coordinated with exit from cell cycle (11,12), and therefore involves crosstalk between the molecular pathways controlling proliferation and differentiation. Because let-7 miRNAs are tightly governed by Lin28a in neural stem cells, a prompt mechanism is required to respond to environmental signal and attenuate the inhibitory effect of Lin28a. On the other hand, mit...

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Section: Discussionmentioning

confidence: 99%

Section: Edited By Roger J Colbranmentioning

confidence: 99%

Extracellular Signal-regulated Kinases (ERKs) Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation

Lei

Chen

et al. 2017

Journal of Biological Chemistry

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“…Premature disruption or delayed initiation of these developmental processes alters the number of neuronal types or subtypes produced, affects neuronal connectivity and can lead to neurological dysfunction. Over the recent years, a number of studies have shown that key regulators of cell cycle progression influence neural cell fate and differentiation and conversely, cell fate determinants and differentiation-inducing proteins regulate the cell cycle [for reviews see 1-4]. …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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“…Neurons are fully differentiated and do not divide in adults, and so they are considered in G 0 phase. The postmitotic state in neurons is maintained by p27 and p21 and sequestration of cyclin D in the cytoplasm (Politis et al 2008). Less is known about the cell cycle status of fibroblasts in humans, although they are assumed to be nondividing unless triggered to proliferate by trauma or increase in body size.…”

Section: Characterization Of the Cell Cycle In Vzv Host Cellsmentioning

confidence: 99%

Effects of Varicella-Zoster Virus on Cell Cycle Regulatory Pathways

Moffat

Greenblatt

2010

Current Topics in Microbiology and Immunology

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Varicella-zoster virus (VZV) grows efficiently in quiescent cells in vivo and in culture, and virus infection activates cell cycle and signaling pathways without cell division. VZV ORFs have been identified that determine the tissue tropism for nondividing skin, T cells, and neurons in SCID-Hu mouse models. The normal cell cycle status of human foreskin fibroblasts was characterized and was dysregulated upon infection by VZV. The expression of cyclins A, B1, and D3 was highly elevated but did not correspond with extensive cellular DNA synthesis. Cell cycle arrest may be due to activation of the DNA damage response during VZV DNA replication. Other host regulatory proteins were induced in infected cells, including p27, p53, and ATM kinase. A possible explanation for the increase in cell cycle regulatory proteins is activation of transcription factors during VZV infection. There is evidence that VZV infection activates transcription factors through the mitogen-activated protein kinase pathways extracellular-regulated kinase (ERK) and c-Jun N-terminal (transpose these parts of the compound noun) kinase (JNK), which could selectively increase cyclin levels. Some of these perturbed cell functions are essential for VZV replication, such as cyclin-dependent kinase (CDK) activity, and reveal targets for interventions.

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Coordination of cell cycle exit and differentiation of neuronal progenitors

Cited by 39 publications

References 98 publications

Extracellular Signal-regulated Kinases (ERKs) Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation

Extracellular Signal-regulated Kinases (ERKs) Phosphorylate Lin28a Protein to Modulate P19 Cell Proliferation and Differentiation

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

Effects of Varicella-Zoster Virus on Cell Cycle Regulatory Pathways

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