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Article ; Online: Better together: Unifying discordant cell-cycle oscillator models.

Pomerening, Joseph R

2018 Volume 17, Issue 1, Page(s) 9–10

MeSH term(s)	Cell Cycle ; Cyclins
Chemical Substances	Cyclins
Language	English
Publishing date	2018-01-02
Publishing country	United States
Document type	News ; Comment
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2017.1389197
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Article ; Online: Positive-feedback loops in cell cycle progression.

Pomerening, Joseph R

FEBS letters

2009 Volume 583, Issue 21, Page(s) 3388–3396

Abstract: A positive-feedback loop is a simple motif that is ubiquitous to the modules and networks that comprise cellular signaling systems. Signaling behaviors that are synonymous with positive feedback include amplification and rapid switching, maintenance, and ...

Abstract	A positive-feedback loop is a simple motif that is ubiquitous to the modules and networks that comprise cellular signaling systems. Signaling behaviors that are synonymous with positive feedback include amplification and rapid switching, maintenance, and the coherence of outputs. Recent advances have been made towards understanding how positive-feedback loops function, as well as their mechanistic basis in controlling eukaryotic cell cycle progression. Some of these advances will be reviewed here, including: how cyclin controls passage through Start and maintains coherence of G1/S regulon expression in yeast; how Polo-like kinase 1 activation is driven by Bora and Aurora A, and its expression is stimulated by Forkhead Box M1 in mammalian cells; and how some of the various dynamic behaviors of spindle assembly and anaphase onset can be produced.
MeSH term(s)	Animals ; Cell Cycle/genetics ; Feedback, Physiological/genetics ; Gene Expression Regulation ; Humans ; Mitosis ; Regulon/genetics
Language	English
Publishing date	2009-10-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2009.10.001
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Article: Uncovering mechanisms of bistability in biological systems.

Pomerening, Joseph R

Current opinion in biotechnology

2008 Volume 19, Issue 4, Page(s) 381–388

Abstract: As the systems biology era progresses, theoreticians and experimentalists continue uncovering the molecular mechanisms that underlie the regulation of complex cellular phenomena, including those governing proliferation, differentiation, and death. The ... ...

Abstract	As the systems biology era progresses, theoreticians and experimentalists continue uncovering the molecular mechanisms that underlie the regulation of complex cellular phenomena, including those governing proliferation, differentiation, and death. The discovery of bistability in cellular responses and their signaling pathways has become a recurring theme, and prompted strong interest in understanding both the design and function of these networks. Modeling these systems has been crucial in assisting experimentalists to better understand how this and other types of behavior can emerge from a subset of regulators, and also to analyze and identify systems-level characteristics that would otherwise be difficult to intuit. In this review, recent advances in both theoretical and experimental work investigating the mechanistic as well as biological basis for bistability will be presented. These will include the role of positive feedback loops, the potential function of dual phosphorylation cycles, and substrate competition as a means of generating ultrasensitivity.
MeSH term(s)	Cell Division ; Phosphorylation ; Systems Biology
Language	English
Publishing date	2008-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1052045-4
ISSN	1879-0429 ; 0958-1669
ISSN (online)	1879-0429
ISSN	0958-1669
DOI	10.1016/j.copbio.2008.06.009
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Article ; Online: Punctuated cyclin synthesis drives early embryonic cell cycle oscillations.

Kang, Qing / Pomerening, Joseph R

Molecular biology of the cell

2011 Volume 23, Issue 2, Page(s) 284–296

Abstract: Cyclin B activates cyclin-dependent kinase 1 (CDK1) at mitosis, but conflicting views have emerged on the dynamics of its synthesis during embryonic cycles, ranging from continuous translation to rapid synthesis during mitosis. Here we show that a CDK1- ... ...

Abstract	Cyclin B activates cyclin-dependent kinase 1 (CDK1) at mitosis, but conflicting views have emerged on the dynamics of its synthesis during embryonic cycles, ranging from continuous translation to rapid synthesis during mitosis. Here we show that a CDK1-mediated negative-feedback loop attenuates cyclin production before mitosis. Cyclin B plateaus before peak CDK1 activation, and proteasome inhibition caused minimal accumulation during mitosis. Inhibiting CDK1 permitted continual cyclin B synthesis, whereas adding nondegradable cyclin stalled it. Cycloheximide treatment before mitosis affected neither cyclin levels nor mitotic entry, corroborating this repression. Attenuated cyclin production collaborates with its destruction, since excess cyclin B1 mRNA accelerated cyclin synthesis and caused incomplete proteolysis and mitotic arrest. This repression involved neither adenylation nor the 3' untranslated region, but it corresponded with a shift in cyclin B1 mRNA from polysome to nonpolysome fractions. A pulse-driven CDK1-anaphase-promoting complex (APC) model corroborated these results, revealing reduced cyclin levels during an oscillation and permitting more effective removal. This design also increased the robustness of the oscillator, with lessened sensitivity to changes in cyclin synthesis rate. Taken together, the results of this study underscore that attenuating cyclin synthesis late in interphase improves both the efficiency and robustness of the CDK1-APC oscillator.
MeSH term(s)	Adenosine Monophosphate/metabolism ; Animals ; CDC2 Protein Kinase/metabolism ; Cell Cycle ; Cell Division ; Cyclin B/biosynthesis ; Embryo, Nonmammalian/cytology ; Embryo, Nonmammalian/metabolism ; Feedback, Physiological ; Mitosis ; Polyribosomes/metabolism ; Protein Biosynthesis ; RNA, Messenger/metabolism ; Xenopus laevis
Chemical Substances	Cyclin B ; RNA, Messenger ; Adenosine Monophosphate (415SHH325A) ; CDC2 Protein Kinase (EC 2.7.11.22)
Language	English
Publishing date	2011-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E11-09-0768
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Article ; Online: Evidence toward a dual phosphatase mechanism that restricts Aurora A (Thr-295) phosphorylation during the early embryonic cell cycle.

Kang, Qing / Srividhya, Jeyaraman / Ipe, Joseph / Pomerening, Joseph R

The Journal of biological chemistry

2014 Volume 289, Issue 25, Page(s) 17480–17496

Abstract: The mitotic kinase Aurora A (AurA) is regulated by a complex network of factors that includes co-activator binding, autophosphorylation, and dephosphorylation. Dephosphorylation of AurA by PP2A (human, Ser-51; Xenopus, Ser-53) destabilizes the protein, ... ...

Abstract	The mitotic kinase Aurora A (AurA) is regulated by a complex network of factors that includes co-activator binding, autophosphorylation, and dephosphorylation. Dephosphorylation of AurA by PP2A (human, Ser-51; Xenopus, Ser-53) destabilizes the protein, whereas mitotic dephosphorylation of its T-loop (human, Thr-288; Xenopus, Thr-295) by PP6 represses AurA activity. However, AurA(Thr-295) phosphorylation is restricted throughout the early embryonic cell cycle, not just during M-phase, and how Thr-295 is kept dephosphorylated during interphase and whether or not this mechanism impacts the cell cycle oscillator were unknown. Titration of okadaic acid (OA) or fostriecin into Xenopus early embryonic extract revealed that phosphatase activity other than PP1 continuously suppresses AurA(Thr-295) phosphorylation during the early embryonic cell cycle. Unexpectedly, we observed that inhibiting a phosphatase activity highly sensitive to OA caused an abnormal increase in AurA(Thr-295) phosphorylation late during interphase that corresponded with delayed cyclin-dependent kinase 1 (CDK1) activation. AurA(Thr-295) phosphorylation indeed influenced this timing, because AurA isoforms retaining an intact Thr-295 residue further delayed M-phase entry. Using mathematical modeling, we determined that one phosphatase would be insufficient to restrict AurA phosphorylation and regulate CDK1 activation, whereas a dual phosphatase topology best recapitulated our experimental observations. We propose that two phosphatases target Thr-295 of AurA to prevent premature AurA activation during interphase and that phosphorylated AurA(Thr-295) acts as a competitor substrate with a CDK1-activating phosphatase in late interphase. These results suggest a novel relationship between AurA and protein phosphatases during progression throughout the early embryonic cell cycle and shed new light on potential defects caused by AurA overexpression.
MeSH term(s)	Animals ; Aurora Kinase A/genetics ; Aurora Kinase A/metabolism ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; Cell Cycle/physiology ; Dual-Specificity Phosphatases/genetics ; Dual-Specificity Phosphatases/metabolism ; Embryo, Nonmammalian/cytology ; Embryo, Nonmammalian/enzymology ; Enzyme Activation/physiology ; Gene Expression Regulation, Developmental/physiology ; Gene Expression Regulation, Enzymologic/physiology ; Phosphorylation/physiology ; Threonine/genetics ; Threonine/metabolism ; Xenopus Proteins/genetics ; Xenopus Proteins/metabolism ; Xenopus laevis
Chemical Substances	Xenopus Proteins ; Threonine (2ZD004190S) ; Aurora Kinase A (EC 2.7.11.1) ; CDC2 Protein Kinase (EC 2.7.11.22) ; Dual-Specificity Phosphatases (EC 3.1.3.48)
Language	English
Publishing date	2014-05-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.527622
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Article ; Online: Open cascades as simple solutions to providing ultrasensitivity and adaptation in cellular signaling.

Srividhya, Jeyaraman / Li, Yongfeng / Pomerening, Joseph R

Physical biology

2011 Volume 8, Issue 4, Page(s) 46005

Abstract: Cell signaling is achieved predominantly by reversible phosphorylation-dephosphorylation reaction cascades. Up until now, circuits conferring adaptation have all required the presence of a cascade with some type of closed topology: negative-feedback loop ...

Abstract	Cell signaling is achieved predominantly by reversible phosphorylation-dephosphorylation reaction cascades. Up until now, circuits conferring adaptation have all required the presence of a cascade with some type of closed topology: negative-feedback loop with a buffering node, or incoherent feed-forward loop with a proportioner node. In this paper--using Goldbeter and Koshland-type expressions--we propose a differential equation model to describe a generic, open signaling cascade that elicits an adaptation response. This is accomplished by coupling N phosphorylation-dephosphorylation cycles unidirectionally, without any explicit feedback loops. Using this model, we show that as the length of the cascade grows, the steady states of the downstream cycles reach a limiting value. In other words, our model indicates that there are a minimum number of cycles required to achieve a maximum in sensitivity and amplitude in the response of a signaling cascade. We also describe for the first time that the phenomenon of ultrasensitivity can be further subdivided into three sub-regimes, separated by sharp stimulus threshold values: OFF, OFF-ON-OFF, and ON. In the OFF-ON-OFF regime, an interesting property emerges. In the presence of a basal amount of activity, the temporal evolution of early cycles yields damped peak responses. On the other hand, the downstream cycles switch rapidly to a higher activity state for an extended period of time, prior to settling to an OFF state (OFF-ON-OFF). This response arises from the changing dynamics between a feed-forward activation module and dephosphorylation reactions. In conclusion, our model gives the new perspective that open signaling cascades embedded in complex biochemical circuits may possess the ability to show a switch-like adaptation response, without the need for any explicit feedback circuitry.
MeSH term(s)	Adaptation, Physiological ; Animals ; Computer Simulation ; Humans ; Kinetics ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/metabolism ; Models, Biological ; Phosphorylation ; Proteins/metabolism ; Signal Transduction
Chemical Substances	Proteins ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2011-05-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2133216-2
ISSN	1478-3975 ; 1478-3967
ISSN (online)	1478-3975
ISSN	1478-3967
DOI	10.1088/1478-3975/8/4/046005
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Article ; Online: Expression of constitutively active CDK1 stabilizes APC-Cdh1 substrates and potentiates premature spindle assembly and checkpoint function in G1 cells.

Ma, Yan / Yuan, Xi / Wyatt, William R / Pomerening, Joseph R

PloS one

2012 Volume 7, Issue 3, Page(s) e33835

Abstract: Mitotic progression in eukaryotic cells depends upon the activation of cyclin-dependent kinase 1 (CDK1), followed by its inactivation through the anaphase-promoting complex (APC)/cyclosome-mediated degradation of M-phase cyclins. Previous work revealed ... ...

Abstract	Mitotic progression in eukaryotic cells depends upon the activation of cyclin-dependent kinase 1 (CDK1), followed by its inactivation through the anaphase-promoting complex (APC)/cyclosome-mediated degradation of M-phase cyclins. Previous work revealed that expression of a constitutively active CDK1 (CDK1AF) in HeLa cells permitted their division, but yielded G1 daughter cells that underwent premature S-phase and early mitotic events. While CDK1AF was found to impede the sustained activity of APC-Cdh1, it was unknown if this defect improperly stabilized mitotic substrates and contributed to the occurrence of these premature M phases. Here, we show that CDK1AF expression in HeLa cells improperly stabilized APC-Cdh1 substrates in G1-phase daughter cells, including mitotic kinases and the APC adaptor, Cdc20. Division of CDK1AF-expressing cells produced G1 daughters with an accelerated S-phase onset, interrupted by the formation of premature bipolar spindles capable of spindle assembly checkpoint function. Further characterization of these phenotypes induced by CDK1AF expression revealed that this early spindle formation depended upon premature CDK1 and Aurora B activities, and their inhibition induced rapid spindle disassembly. Following its normal M-phase degradation, we found that the absence of Wee1 in these prematurely cycling daughter cells permitted the endogenous CDK1 to contribute to these premature mitotic events, since expression of a non-degradable Wee1 reduced the number of cells that exhibited premature cyclin B1oscillations. Lastly, we discovered that Cdh1-ablated cells could not be forced into a premature M phase, despite cyclin B1 overexpression and proteasome inhibition. Together, these results demonstrate that expression of constitutively active CDK1AF hampers the destruction of critical APC-Cdh1 targets, and that this type of condition could prevent newly divided cells from properly maintaining a prolonged interphase state. We propose that this more subtle type of defect in activity of the APC-driven negative-feedback loop may have implications for triggering genome instability and tumorigenesis.
MeSH term(s)	Anaphase-Promoting Complex-Cyclosome ; Aurora Kinase B ; Aurora Kinases ; CDC2 Protein Kinase/metabolism ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Chromatin Assembly and Disassembly ; Cyclin B1/genetics ; Cyclin B1/metabolism ; DNA Replication ; Enzyme Stability ; G1 Phase Cell Cycle Checkpoints/physiology ; Gene Expression ; Gene Silencing ; Genomic Instability ; HeLa Cells ; Humans ; M Phase Cell Cycle Checkpoints ; Mad2 Proteins ; Mitosis ; Mutation ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Proteasome Inhibitors ; Protein Transport ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Spindle Apparatus/metabolism ; Ubiquitin-Protein Ligase Complexes/metabolism
Chemical Substances	Calcium-Binding Proteins ; Cell Cycle Proteins ; Cyclin B1 ; MAD2L1 protein, human ; Mad2 Proteins ; Nuclear Proteins ; Proteasome Inhibitors ; Repressor Proteins ; Ubiquitin-Protein Ligase Complexes (EC 2.3.2.23) ; Anaphase-Promoting Complex-Cyclosome (EC 2.3.2.27) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; WEE1 protein, human (EC 2.7.10.2) ; AURKB protein, human (EC 2.7.11.1) ; Aurora Kinase B (EC 2.7.11.1) ; Aurora Kinases (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; CDC2 Protein Kinase (EC 2.7.11.22)
Language	English
Publishing date	2012-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0033835
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Article ; Online: Rapid cycling and precocious termination of G1 phase in cells expressing CDK1AF.

Pomerening, Joseph R / Ubersax, Jeffrey A / Ferrell, James E

Molecular biology of the cell

2008 Volume 19, Issue 8, Page(s) 3426–3441

Abstract: In Xenopus embryos, the cell cycle is driven by an autonomous biochemical oscillator that controls the periodic activation and inactivation of cyclin B1-CDK1. The oscillator circuit includes a system of three interlinked positive and double-negative ... ...

Abstract	In Xenopus embryos, the cell cycle is driven by an autonomous biochemical oscillator that controls the periodic activation and inactivation of cyclin B1-CDK1. The oscillator circuit includes a system of three interlinked positive and double-negative feedback loops (CDK1 -> Cdc25 -> CDK1; CDK1 -/ Wee1 -/ CDK1; and CDK1 -/ Myt1 -/ CDK1) that collectively function as a bistable trigger. Previous work established that this bistable trigger is essential for CDK1 oscillations in the early embryonic cell cycle. Here, we assess the importance of the trigger in the somatic cell cycle, where checkpoints and additional regulatory mechanisms could render it dispensable. Our approach was to express the phosphorylation site mutant CDK1AF, which short-circuits the feedback loops, in HeLa cells, and to monitor cell cycle progression by live cell fluorescence microscopy. We found that CDK1AF-expressing cells carry out a relatively normal first mitosis, but then undergo rapid cycles of cyclin B1 accumulation and destruction at intervals of 3-6 h. During these cycles, the cells enter and exit M phase-like states without carrying out cytokinesis or karyokinesis. Phenotypically similar rapid cycles were seen in Wee1 knockdown cells. These findings show that the interplay between CDK1, Wee1/Myt1, and Cdc25 is required for the establishment of G1 phase, for the normal approximately 20-h cell cycle period, and for the switch-like oscillations in cyclin B1 abundance characteristic of the somatic cell cycle. We propose that the HeLa cell cycle is built upon an unreliable negative feedback oscillator and that the normal high reliability, slow pace and switch-like character of the cycle is imposed by a bistable CDK1/Wee1/Myt1/Cdc25 system.
MeSH term(s)	Animals ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; Cell Cycle ; Cell Cycle Proteins/metabolism ; Cyclin B/metabolism ; Cyclin B1 ; G1 Phase ; Gene Expression Regulation ; Gene Expression Regulation, Developmental ; HeLa Cells ; Humans ; Mitosis ; Models, Biological ; Mutation ; Nuclear Proteins/metabolism ; Protein-Tyrosine Kinases/metabolism ; Time Factors ; Xenopus
Chemical Substances	CCNB1 protein, human ; Cell Cycle Proteins ; Cyclin B ; Cyclin B1 ; Nuclear Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; WEE1 protein, human (EC 2.7.10.2) ; CDC2 Protein Kinase (EC 2.7.11.22)
Language	English
Publishing date	2008-05-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E08-02-0172
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Article ; Online: Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset.

Yuan, Xi / Srividhya, Jeyaraman / De Luca, Thomas / Lee, Ju-Hyong E / Pomerening, Joseph R

Molecular biology of the cell

2013 Volume 25, Issue 4, Page(s) 441–456

Abstract: Cdh1, a coactivator of the anaphase-promoting complex (APC), is a potential tumor suppressor. Cdh1 ablation promotes precocious S-phase entry, but it was unclear how this affects DNA replication dynamics while contributing to genomic instability and ... ...

Abstract	Cdh1, a coactivator of the anaphase-promoting complex (APC), is a potential tumor suppressor. Cdh1 ablation promotes precocious S-phase entry, but it was unclear how this affects DNA replication dynamics while contributing to genomic instability and tumorigenesis. We find that Cdh1 depletion causes early S-phase onset in conjunction with increase in Rb/E2F1-mediated cyclin E1 expression, but reduced levels of cyclin E1 protein promote this transition. We hypothesize that this is due to a weakened cyclin-dependent kinase inhibitor (CKI)-cyclin-dependent kinase 2 positive-feedback loop, normally generated by APC-Cdh1-mediated proteolysis of Skp2. Indeed, Cdh1 depletion increases Skp2 abundance while diminishing levels of the CKI p27. This lowers the level of cyclin E1 needed for S-phase entry and delays cyclin E1 proteolysis during S-phase progression while corresponding to slowed replication fork movement and reduced frequency of termination events. In summary, using both experimental and computational approaches, we show that APC-Cdh1 establishes a stimulus-response relationship that promotes S phase by ensuring that proper levels of p27 accumulate during G1 phase, and defects in its activation accelerate the timing of S-phase onset while prolonging its progression.
MeSH term(s)	Anaphase-Promoting Complex-Cyclosome/genetics ; Anaphase-Promoting Complex-Cyclosome/metabolism ; Antigens, CD ; Cadherins/antagonists & inhibitors ; Cadherins/genetics ; Cadherins/metabolism ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; Cyclin E/genetics ; Cyclin E/metabolism ; Cyclin-Dependent Kinase 2/genetics ; Cyclin-Dependent Kinase 2/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/genetics ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; DNA Replication ; E2F1 Transcription Factor/genetics ; E2F1 Transcription Factor/metabolism ; Feedback, Physiological ; G1 Phase ; Gene Expression Regulation ; HeLa Cells ; Humans ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Proteolysis ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; S Phase ; S-Phase Kinase-Associated Proteins/genetics ; S-Phase Kinase-Associated Proteins/metabolism ; Signal Transduction ; Time Factors
Chemical Substances	Antigens, CD ; CCNE1 protein, human ; CDH1 protein, human ; Cadherins ; Cyclin E ; E2F1 Transcription Factor ; E2F1 protein, human ; Oncogene Proteins ; RNA, Small Interfering ; Retinoblastoma Protein ; S-Phase Kinase-Associated Proteins ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Anaphase-Promoting Complex-Cyclosome (EC 2.3.2.27) ; CDK2 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22)
Language	English
Publishing date	2013-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E13-08-0480
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Article ; Online: Expression of constitutively active CDK1 stabilizes APC-Cdh1 substrates and potentiates premature spindle assembly and checkpoint function in G1 cells.

Yan Ma / Xi Yuan / William R Wyatt / Joseph R Pomerening

PLoS ONE, Vol 7, Iss 3, p e

2012 Volume 33835

Abstract	Mitotic progression in eukaryotic cells depends upon the activation of cyclin-dependent kinase 1 (CDK1), followed by its inactivation through the anaphase-promoting complex (APC)/cyclosome-mediated degradation of M-phase cyclins. Previous work revealed that expression of a constitutively active CDK1 (CDK1AF) in HeLa cells permitted their division, but yielded G1 daughter cells that underwent premature S-phase and early mitotic events. While CDK1AF was found to impede the sustained activity of APC-Cdh1, it was unknown if this defect improperly stabilized mitotic substrates and contributed to the occurrence of these premature M phases. Here, we show that CDK1AF expression in HeLa cells improperly stabilized APC-Cdh1 substrates in G1-phase daughter cells, including mitotic kinases and the APC adaptor, Cdc20. Division of CDK1AF-expressing cells produced G1 daughters with an accelerated S-phase onset, interrupted by the formation of premature bipolar spindles capable of spindle assembly checkpoint function. Further characterization of these phenotypes induced by CDK1AF expression revealed that this early spindle formation depended upon premature CDK1 and Aurora B activities, and their inhibition induced rapid spindle disassembly. Following its normal M-phase degradation, we found that the absence of Wee1 in these prematurely cycling daughter cells permitted the endogenous CDK1 to contribute to these premature mitotic events, since expression of a non-degradable Wee1 reduced the number of cells that exhibited premature cyclin B1oscillations. Lastly, we discovered that Cdh1-ablated cells could not be forced into a premature M phase, despite cyclin B1 overexpression and proteasome inhibition. Together, these results demonstrate that expression of constitutively active CDK1AF hampers the destruction of critical APC-Cdh1 targets, and that this type of condition could prevent newly divided cells from properly maintaining a prolonged interphase state. We propose that this more subtle type of defect in activity of the ...
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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