Cell cycle arrest induced by ectopic expression of p27 is not sufficient to promote oligodendrocyte differentiation

Xm, Tang; Js, Beesley; Jb, Grinspan; Seth, Prem; Kamholz, John; Cambi, Franca

doi:10.1002/(sici)1097-4644(20000201)76:2<270::aid-jcb10>3.0.co;2-6

Cited by 46 publications

(33 citation statements)

References 58 publications

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“…In our OP cultures, IFNG increased apoptotic cell death but not differentiation, consistent with a prior report that oligodendroglial differentiation requires additional signal(s) in conjunction with cell cycle arrest (60). Even in control cultures, however, our data clearly demonstrated that a small proportion of OP continuously died of apoptosis at a constant rate.…”

Section: Discussionsupporting

confidence: 91%

MEK-ERK Signaling Is Involved in Interferon-γ-induced Death of Oligodendroglial Progenitor Cells*

Horiuchi

Itoh

Pleasure

et al. 2006

Journal of Biological Chemistry

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Oligodendrocytes are exposed to various cytokines in inflammatory lesions in the central nervous system. In this study, we focused on the direct effects of interferon-␥ (IFNG) on highly purified rat oligodendroglial cultures at different developmental stages. Among the three stages tested, IFNG had direct cytotoxic effects on actively proliferating oligodendrocyte progenitors but much less on immature oligodendrocytes and none on mature oligodendrocytes. This stage-specific susceptibility of progenitors to IFNG-induced cytotoxicity consisted of two components, delay in the G 1 /S transition of the cell cycle and increased cell death at least partly mediated by apoptosis, suggesting that progression of the cell cycle was tightly linked to this toxic mechanism. There was no functional difference in the signal transducers and activators of transcription (STAT) pathways between progenitors and mature oligodendrocytes as determined by induction of IRF1 mRNA in response to IFNG. We found that partial inhibition of the MEK-ERK pathway, one of the mitogen-activated protein kinase phosphorelay modules, by U0126 partially reversed the IFNG-induced cytotoxicity in progenitors. In addition, ERK activity was quickly down-regulated after in vitro differentiation of progenitors to immature oligodendrocytes. Therefore, we concluded that simultaneous activation of the STAT pathway by IFNG and of the ERK pathway by exogenous trophic factors played a role in the stage-specific IFNG-induced cytotoxicity in oligodendroglial progenitors. Our study has implications with respect to the mechanisms of periventricular leukomalacia in infants and of persistent demyelination in multiple sclerosis lesions in adults.

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Section: Discussionsupporting

confidence: 91%

MEK-ERK Signaling Is Involved in Interferon-γ-induced Death of Oligodendroglial Progenitor Cells*

Horiuchi

Itoh

Pleasure

et al. 2006

Journal of Biological Chemistry

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“…Kip1 is also a key element in cell cycle progression in many cell types, including oligodendrocytes (36,38). This role is consistent with the major role played by the Cdk2-cyclin E complex in oligodendrocyte progenitor cell cycle progression (15).…”

Section: Discussionsupporting

confidence: 75%

The Sp1 Family of Transcription Factors Is Involved in p27^Kip1-Mediated Activation of Myelin Basic Protein Gene Expression

Wei

Miskimins

2003

Molecular and Cellular Biology

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p27Kip1 levels increase in many cells as they leave the cell cycle and begin to differentiate. The increase in p27Kip1 levels generally precedes the expression of differentiation-specific genes. Previous studies from our laboratory showed that the overexpression of p27 Kip1 enhances myelin basic protein (MBP) promoter activity. This activation is specific to p27Kip1 . Additionally, inhibition of cyclin-dependent kinase activity alone is not sufficient to increase MBP expression. In this study, we focused on understanding how p27 Kip1 involves a novel mechanism that is mediated through the stabilization and binding of transcription factor Sp1.

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“…Thus, the transition of OPCs from proliferation to differentiation is a key step that governs central nervous system myelin development (5,6). However, forced cell cycle exit is not sufficient for inducing OPC differentiation (7,8), suggesting the existence of cell cycle-independent yet undefined mechanisms that directly promote OPC differentiation/maturation.…”

mentioning

confidence: 99%

The Selective RNA-binding Protein Quaking I (QKI) Is Necessary and Sufficient for Promoting Oligodendroglia Differentiation

Chen

Tian

et al. 2007

Journal of Biological Chemistry

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Quaking I (QKI) is a selective RNA-binding protein essential for myelination of the central nervous system. Three QKI isoforms with distinct C termini and subcellular localization, namely QKI-5, QKI-6, and QKI-7, are expressed in oligodendroglia progenitor cells (OPCs) prior to the initiation of myelin formation and implicated in promoting oligodendrocyte lineage development. However, the functional requirement for each QKI isoform and the mechanisms by which QKI isoforms govern OPC development still remain elusive. We report here that exogenous expression of each QKI isoform is sufficient to enhance differentiation of OPCs with different efficiency, which is abolished by a point mutation that abrogates the RNA binding activity of QKI. Reciprocally, small interfering RNA-mediated QKI knockdown blocks OPC differentiation, which can be partly rescued by QKI-5 and QKI-6 but not by QKI-7, indicating the differential requirement of QKI isoform function in advancing OPC differentiation. Furthermore, we found that abrogation of OPC differentiation, as a result of QKI deficiency, is not due to altered proliferation capacity or cell cycle progression. These results indicate that QKI isoforms are necessary and sufficient for promoting OPC development, which must involve direct influence of QKI on differentiation/maturation of OPCs independent of cell cycle exit, likely via regulating the expression of the target mRNAs of QKI that support OPC differentiation.

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Cell cycle arrest induced by ectopic expression of p27 is not sufficient to promote oligodendrocyte differentiation

Cited by 46 publications

References 58 publications

MEK-ERK Signaling Is Involved in Interferon-γ-induced Death of Oligodendroglial Progenitor Cells*

MEK-ERK Signaling Is Involved in Interferon-γ-induced Death of Oligodendroglial Progenitor Cells*

The Sp1 Family of Transcription Factors Is Involved in p27^Kip1-Mediated Activation of Myelin Basic Protein Gene Expression

The Selective RNA-binding Protein Quaking I (QKI) Is Necessary and Sufficient for Promoting Oligodendroglia Differentiation

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Cell cycle arrest induced by ectopic expression of p27 is not sufficient to promote oligodendrocyte differentiation

Cited by 46 publications

References 58 publications

MEK-ERK Signaling Is Involved in Interferon-γ-induced Death of Oligodendroglial Progenitor Cells*

MEK-ERK Signaling Is Involved in Interferon-γ-induced Death of Oligodendroglial Progenitor Cells*

The Sp1 Family of Transcription Factors Is Involved in p27Kip1-Mediated Activation of Myelin Basic Protein Gene Expression

The Selective RNA-binding Protein Quaking I (QKI) Is Necessary and Sufficient for Promoting Oligodendroglia Differentiation

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The Sp1 Family of Transcription Factors Is Involved in p27^Kip1-Mediated Activation of Myelin Basic Protein Gene Expression