Conditional Tet-Regulated Over-Expression of Hoxa2 in CG4 Cells Increases Their Proliferation and Delays Their Differentiation into Oligodendrocyte-like Cells Expressing Myelin Basic Protein

Wang, Monica; Doucette, J. Ronald; Nazarali, Adil J.

doi:10.1007/s10571-011-9685-2

Cited by 4 publications

(8 citation statements)

References 85 publications

(96 reference statements)

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“…Indeed, p53 is known to be mainly involved in cell cycle arrest, senescence and apoptosis [67]. Thus, a p53 stabilization would, at a first glance, induce cell cycle arrest, senescence and/or increase in apoptosis, which is not in line with Hoxa2 functional studies that led to postulate anti-differentiation and pro-proliferative roles for Hoxa2 [43,46,68]. Nevertheless, besides its role in cell cycle and apoptosis, p53 has also been involved in DNA repair.…”

Section: Discussionmentioning

confidence: 99%

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The Homeodomain Transcription Factor Hoxa2 Interacts with and Promotes the Proteasomal Degradation of the E3 Ubiquitin Protein Ligase RCHY1

et al. 2013

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Hox proteins are conserved homeodomain transcription factors known to be crucial regulators of animal development. As transcription factors, the functions and modes of action (co-factors, target genes) of Hox proteins have been very well studied in a multitude of animal models. However, a handful of reports established that Hox proteins may display molecular activities distinct from gene transcription regulation. Here, we reveal that Hoxa2 interacts with 20S proteasome subunits and RCHY1 (also known as PIRH2), an E3 ubiquitin ligase that targets p53 for degradation. We further show that Hoxa2 promotes proteasome-dependent degradation of RCHY1 in an ubiquitin-independent manner. Correlatively, Hoxa2 alters the RCHY1-mediated ubiquitination of p53 and promotes p53 stabilization. Together, our data establish that Hoxa2 can regulate the proteasomal degradation of RCHY1 and stabilization of p53.

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Section: Discussionmentioning

confidence: 99%

“…Hoxa2 also inhibits differentiation of oligodendrocytes and, in addition, promotes their proliferation [46,47]. Conversely, Hoxa2 has been proposed to display an anti-proliferative activity during lung development [48].…”

Section: Introductionmentioning

confidence: 99%

The Homeodomain Transcription Factor Hoxa2 Interacts with and Promotes the Proteasomal Degradation of the E3 Ubiquitin Protein Ligase RCHY1

et al. 2013

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“…For this purpose, we measured the expression of two major myelin genes, myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP), in the differentiated CG4 oligodendrocytic cell line, with or without EPOR expression. CG4 cells are considered a good tool to study myelination in vitro (25,26). We also investigated the role of early growth response gene 2 (Egr2), a gene required for myelination in the peripheral nervous system (27), whose expression is induced by EPO in the brain (6).…”

Section: Erythropoietin (Epo) Increases Myelin Gene Expression In Cg4mentioning

confidence: 99%

Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

Cervellini

Annenkov

Brenton

et al. 2013

Mol Med

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Erythropoietin (EPO) has protective effects in neurodegenerative and neuroinflammatory diseases, including in animal models of multiple sclerosis, where EPO decreases disease severity. EPO also promotes neurogenesis and is protective in models of toxic demyelination. In this study, we asked whether EPO could promote neurorepair by also inducing remyelination. In addition, we investigated whether the effect of EPO could be mediated by the classical erythropoietic EPO receptor (EPOR), since it is still questioned if EPOR is functional in nonhematopoietic cells. Using CG4 cells, a line of rat oligodendrocyte precursor cells, we found that EPO increases the expression of myelin genes (myelin oligodendrocyte glycoprotein [MOG] and myelin basic protein [MBP]). EPO had no effect in wild-type CG4 cells, which do not express EPOR, whereas it increased MOG and MBP expression in cells engineered to overexpress EPOR (CG4-EPOR). This was reflected in a marked increase in MOG protein levels, as detected by Western blot. In these cells, EPO induced by 10-fold the early growth response gene 2 (Egr2), which is required for peripheral myelination. However, Egr2 silencing with a siRNA did not reverse the effect of EPO, indicating that EPO acts through other pathways. In conclusion, EPO induces the expression of myelin genes in oligodendrocytes and this effect requires the presence of EPOR. This study demonstrates that EPOR can mediate neuroreparative effects.

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“…CG4-OL Cell Culture-CG4-OL is a O-2A progenitor cell line derived from rat brain, cultured and maintained as previ-ously described (31)(32)(33)(34). Briefly, the CG4-OL cells were cultured on poly-D-lysine (Sigma)-coated tissue culture dishes and maintained as undifferentiated progenitors in GM containing Dulbecco's modified Eagle's medium (DMEM), 50 g/ml of transferrin, 5 g/ml of insulin, 9.8 ng/ml of biotin, 50 ng/ml of selenium, 1% antibiotic antimycotic solution, and 30% B104 conditioned medium (31,34). Differentiation of CG4-OL cells was induced by growth in DM containing 2% fetal bovine serum instead of B104-conditioned medium (31,34).…”

Section: Methodsmentioning

confidence: 99%

“…To further investigate the relationship between qkI and Sirt2 in OL development, we used mouse primary OLs and the CG4-OL cell line derived from neonatal rat forebrain O-2A progenitors that undergo defined stages of differentiation under controlled media conditions (31)(32)(33)(34)(35)(36). Coordinated expression of QKI and SIRT2 was observed during differentiation.…”

mentioning

confidence: 99%

RNA-binding Protein Quaking Stabilizes Sirt2 mRNA during Oligodendroglial Differentiation

Thangaraj

Furber

Gan

et al. 2017

Journal of Biological Chemistry

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Myelination is controlled by timely expression of genes involved in the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Sirtuin 2 (SIRT2), a NAD-dependent deacetylase, plays a critical role in OL differentiation by promoting both arborization and downstream expression of myelin-specific genes. However, the mechanisms involved in regulating SIRT2 expression during OL development are largely unknown. The RNA-binding protein quaking (QKI) plays an important role in myelination by post-transcriptionally regulating the expression of several myelin specific genes. In ) mutant mice, SIRT2 protein is severely reduced; however, it is not known whether these genes interact to regulate OL differentiation. Here, we report for the first time that QKI directly binds to mRNA via a common quaking response element (QRE) located in the 3' untranslated region (UTR) to control SIRT2 expression in OL lineage cells. This interaction is associated with increased stability and longer half-lives of and transcripts leading to increased accumulation of transcripts. Consistent with this, overexpression of promoted the expression of mRNA and protein. However, overexpression of the nuclear isoform promoted the expression of mRNA, but not SIRT2 protein, and delayed OL differentiation. These results suggest that the balance in the subcellular distribution and temporal expression of QKI isoforms control the availability of mRNA for translation. Collectively, our study demonstrates that QKI directly plays a crucial role in the post-transcriptional regulation and expression of to facilitate OL differentiation.

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Conditional Tet-Regulated Over-Expression of Hoxa2 in CG4 Cells Increases Their Proliferation and Delays Their Differentiation into Oligodendrocyte-like Cells Expressing Myelin Basic Protein

Cited by 4 publications

References 85 publications

The Homeodomain Transcription Factor Hoxa2 Interacts with and Promotes the Proteasomal Degradation of the E3 Ubiquitin Protein Ligase RCHY1

The Homeodomain Transcription Factor Hoxa2 Interacts with and Promotes the Proteasomal Degradation of the E3 Ubiquitin Protein Ligase RCHY1

Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

RNA-binding Protein Quaking Stabilizes Sirt2 mRNA during Oligodendroglial Differentiation

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