CDK Inhibitors: Cell Cycle Regulators and Beyond

Besson, Arnaud; Dowdy, Steven F.; Roberts, James M.

doi:10.1016/j.devcel.2008.01.013

Cited by 980 publications

(941 citation statements)

References 141 publications

(183 reference statements)

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“…However, no particular mechanisms have yet been suggested, so it may also be possible that the cytoplasmic and membrane-associated POP could participate in cell cycle regulation. In fact, many proteins controlling the cell cycle are known to be localized to the cytoplasm although the proteins involved in DNA synthesis are usually localized to the nucleus (Besson et al, 2008;Kahl and Means, 2003;Sclafani and Holzen, 2007;Wilkinson and Millar, 2000). In case of the mouse placenta, the cytoplasmic POP may play some role in cell cycle regulation, for example, by processing or interacting with other proteins involved in the cell cycle.…”

Section: Molecular Mass Of Popmentioning

confidence: 99%

Localization and subcellular distribution of prolyl oligopeptidase in the mouse placenta

2011

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Prolyl oligopeptidase (POP) is a serine endopeptidase which selectively digests a -Pro-X-peptide bond.Our previous study showed that POP mRNA was strongly expressed in the spongiotrophoblast of the mouse placenta at E17.5, suggesting its importance in development. To gain more insight into POP's role during gestation, we investigated its expression using different developmental stages of placenta. As a result of in situ hybridization, we found that localization of POP mRNA changed at E12.5. POP mRNA was strongly expressed in the spongiotrophoblast and labyrinth at E10.5 and E11.5 but thereafter only in the spongiotrophoblast. Immunohistochemistry revealed that POP was present in the parietal trophoblast giant cell, the spongiotrophoblast cell, and the labyrinth at E11.5 but the strong expression in the labyrinth was maintained only in the canal-associated and sinusoidal trophoblast giant cells at E16.5 and E18.5. To determine subcellular distribution of the POP protein, we fractionated the placental extract into cytoplasmic, membrane, and nuclear subfractions. By Western blot analysis, POP was detected in the cytoplasmic and membrane fractions but not in the nuclear fraction at E11.5 and E16.5. Interestingly, the cytoplasmic POP exhibited higher enzymatic activity than the membrane-associated type. These data suggest that the cytoplasmic and membrane-associated POP have distinct roles in different types of placental cells.

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Section: Molecular Mass Of Popmentioning

confidence: 99%

Localization and subcellular distribution of prolyl oligopeptidase in the mouse placenta

2011

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“…However, in the case of more severe damage, the transient cell-cycle arrest gives way to either apoptotic cell death or a delayed but long-lasting, sometimes irreversible arrest. This long-term arrest can be established in G 1 and G2 phase and relies on the tumor-suppressor protein-53 (p53)-dependent transcriptional activation of p21 Waf1/Cip1 (p21) (Di Leonardo et al, 1994;Waldman et al, 1995;Bunz et al, 1998), a potent inhibitor of CDK activity (Harper et al, 1993;Besson et al, 2008). Cells arrested terminally after p21 induction acquire a senescence-like phenotype, also called premature senescence.…”

Section: Introductionmentioning

confidence: 99%

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

2010

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The long-term cellular response to DNA damage is controlled by the tumor suppressor p53. It results in cellcycle arrest followed by DNA repair and, depending on the degree of damage inflicted, premature senescence or apoptotic cell death. Here we show that in normal diploid fibroblasts the ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C)-Cdh1 becomes prematurely activated in G2 as part of the sustained long-term but not the rapid short-term response to genotoxic stress and results in the degradation of numerous APC/C substrates. Using HCT116 somatic knockout cells we show that mechanistically premature APC/C activation depends on p53 and its transcriptional target p21 that mediates the signal through downregulation of the APC/C inhibitor Emi1. Cdc14B is dispensable in this setting but might function redundantly. Our data suggest an unexpected role for the APC/C in executing a part of the p53-dependent DNA damage response that leads to premature senescence.

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“…The Ink family, composed by p16 Ink4a , p15 Ink4b , p18 Ink4c and p19 Ink4d , regulates the quiescent state by specifically binding to Cdk4/6 thus preventing its union with Cyclin D. 8 The members of the Cip/Kip family, constituted by p21 Cip1 , p27 Kip1 and p57 Kip2 , preferentially inactivate Cyclin/ Cdk complexes but they can also modulate their activity. 3,9 Through all these mechanisms, cell cycle is strictly regulated to obtain 2 daughter cells with the same chromosomal number as that of the original cell.…”

Section: Introductionmentioning

confidence: 99%

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

Ovejero‐Benito

Frade

2015

Cell Cycle

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Nuclear DNA duplication in the absence of cell division (i.e. endoreplication) leads to somatic polyploidy in eukaryotic cells. In contrast to some invertebrate neurons, whose nuclei may contain up to 200,000-fold the normal haploid DNA amount (C), polyploid neurons in higher vertebrates show only 4C DNA content. To explore the mechanism that prevents extra rounds of DNA synthesis in these latter cells we focused on the chick retina, where a population of tetraploid retinal ganglion cells (RGCs) has been described. We show that differentiating chick RGCs that express the neurotrophic receptors p75 and TrkB while lacking retinoblastoma protein, a feature of tetraploid RGCs, also express p27 Kip1 . Two different short hairpin RNAs (shRNA) that significantly downregulate p27 Kip1 expression facilitated DNA synthesis and increased ploidy in isolated chick RGCs. Moreover, this forced DNA synthesis could not be prevented by Cdk4/6 inhibition, thus suggesting that it is triggered by a mechanism similar to endoreplication. In contrast, p27 Kip1 deficiency in mouse RGCs does not lead to increased ploidy despite previous observations have shown ectopic DNA synthesis in RGCs from p27 Kip1¡/¡ mice. This suggests that a differential mechanism is used for the regulation of neuronal endoreplication in mammalian versus avian RGCs.

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CDK Inhibitors: Cell Cycle Regulators and Beyond

Cited by 980 publications

References 141 publications

Localization and subcellular distribution of prolyl oligopeptidase in the mouse placenta

Localization and subcellular distribution of prolyl oligopeptidase in the mouse placenta

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

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CDK Inhibitors: Cell Cycle Regulators and Beyond

Cited by 980 publications

References 141 publications

Localization and subcellular distribution of prolyl oligopeptidase in the mouse placenta

Localization and subcellular distribution of prolyl oligopeptidase in the mouse placenta

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

p27Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells

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p27^Kip1participates in the regulation of endoreplication in differentiating chick retinal ganglion cells