p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity

Kippin, Tod E.; Martens, David J.; Kooy, Derek van der

doi:10.1101/gad.1272305

Cited by 389 publications

(379 citation statements)

References 50 publications

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“…(van Os et al, 2007) Increased neurogenesis and neuronal regeneration, exhaustion of neuronal stem cells during aging. (Pechnick et al, 2008;Kippin et al, 2005;Qiu et al, 2004) Elongated lifespan. Improved maintenance and function of HSCs.…”

Section: Cell Intrinsicmentioning

confidence: 99%

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Song¹,

Ju²,

Rudolph³

2009

Experimental Gerontology

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Section: Cell Intrinsicmentioning

confidence: 99%

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Song¹,

Ju²,

Rudolph³

2009

Experimental Gerontology

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“…Cell cycle dynamics strongly influence neural precursor cell (NPC) maintenance and neurogenesis, [1][2][3][4] and gain-or loss-of-function studies have demonstrated key roles for cell cycle proteins, including the E2f family, in NPC fate decisions. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] E2f3 is required for proper cortical migration of neurons and to maintain the balance between NPC self-renewal, proliferation and differentiation, and its loss disrupts long-term neurogenesis and cortical function; E2f1 deficiency impairs NPC proliferation, and E2f4 deficiency leads to inhibition of NPC self-renewal and severe defects in telencephalic development. 6,[8][9][10]17 A pivotal question is whether cell fate control by the pRb/E2f pathway is largely a consequence of cell cycle regulation, or due to direct regulation of cell fate-associated genes.…”

mentioning

confidence: 99%

Tissue-specific targeting of cell fate regulatory genes by E2f factors

et al. 2015

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Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-β signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell typespecific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues.

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“…p21 is a well-known mediator of p53-dependent cell cycle arrest inhibiting the cyclin-Cdk2 or Cdk4 complexes (Gartel and Radhakrishnan, 2005 for review). It has been shown earlier that p21 can negatively regulate self-renewal of hematopoetic stem cells (Cheng et al, 2000) and adult neural stem cells (Kippin et al, 2005), showing a link between cell cycle regulation and differentiation of adult stem cells.…”

Section: Introductionmentioning

confidence: 99%

Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells

et al. 2008

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p53 is an important regulator of normal cell response to stress and frequently mutated in human tumours. Here, we studied the effects of activation of p53 and its target gene p21 in human embryonic stem cells. We show that activation of p53 with small-molecule activator nutlin leads to rapid differentiation of stem cells evidenced by changes in cell morphology and adhesion, expression of cell-specific markers for primitive endoderm and trophectoderm lineages and loss of pluripotency markers. p21 is quickly and dose-dependently activated by nutlin. It can also be activated independently from p53 by sodium butyrate, which leads to the differentiation events very similar to the ones induced by p53. During differentiation, the activating phosphorylation site of CDK2 Thr-160 becomes dephosphorylated and cyclins A and E become degraded. The target for CDK2 kinase in p53 molecule, Ser-315, also becomes dephosphorylated. We conclude that the main mechanism responsible for differentiation of human stem cells by p53 is abolition of S-phase entry and subsequent stop of cell cycle in G0/G1 phase accompanied by p21 activation.

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p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity

Cited by 389 publications

References 50 publications

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Tissue-specific targeting of cell fate regulatory genes by E2f factors

Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells

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