The cdc25B phosphatase is essential for the G2/M phase transition in human cells

Cdc25 phosphatases play key roles in cell cycle progression by activating cyclin-dependent kinases. In human cells, cdc25 proteins are encoded by a multigene family, consisting of cdc25A, cdc25B and cdc25C. While cdc25A plays a crucial role at the G1/S phase transition, cdc25C is involved in the dephosphorylation and activation of the mitotic kinase, cdc2/cyclinB. In addition, cdc25C itself is regulated by cdc2/cyclinB which then creates a positive feedback loop that controls entry into mitosis. In this study we show that the activity of cdc25B appears during late S phase and peaks during G2 phase. Both in vitro and in vivo cdc25B is activated through phosphorylation during S-phase. Using a cell duplication, microinjection assay we show that ablation of cdc25B function by specific antibodies blocks cell cycle progression in Hs68 cells by inhibition of entry into mitosis. Cdc25B function neither plays a role in later stages of mitosis nor for the inititation of DNA replication. These results indicate that cdc25B is a mitotic regulator that might act as a ‘starter phosphatase’ to initiate the positive feedback loop at the entry into M phase.

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TMOD-02BLOCKING CXCR4 INCREASES SURVIVAL IN A MOUSE MODEL OF NEURAL STEM CELLS-DERIVED GLIOBLASTOMA BY BLOCKING AN AUTOCRINE POSITIVE FEEDBACK LOOP REGULATING APOPTOSIS AND CELL CYCLE PROGRESSION VIA Rb1 AND cdk4/cdk6/CyclinD1

Neuro-Oncology ◽

10.1093/neuonc/nov237.02 ◽

2015 ◽

Vol 17 (suppl 5) ◽

pp. v226.2-v226

Author(s):

Alexandra Calinescu ◽

Erica Carballo ◽

Dustin Tran ◽

Daniel Zamler ◽

Robert Doherty ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Mouse Model ◽

Neural Stem Cells ◽

Positive Feedback ◽

Feedback Loop ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Positive Feedback Loop

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A Positive Feedback Loop between ATOH7 and a Notch Effector Regulates Cell-Cycle Progression and Neurogenesis in the Retina

Cell Reports ◽

10.1016/j.celrep.2013.01.035 ◽

2013 ◽

Vol 3 (3) ◽

pp. 796-807 ◽

Cited By ~ 22

Author(s):

Florence Chiodini ◽

Lidia Matter-Sadzinski ◽

Tania Rodrigues ◽

Dorota Skowronska-Krawczyk ◽

Laurent Brodier ◽

...

Keyword(s):

Cell Cycle ◽

Positive Feedback ◽

Feedback Loop ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Positive Feedback Loop

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Meiotic nuclear divisions 1 (MND1) fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma

Cancer Communications ◽

10.1002/cac2.12155 ◽

2021 ◽

Author(s):

Quanli Zhang ◽

Run Shi ◽

Yongkang Bai ◽

Lijuan Meng ◽

Jingwen Hu ◽

...

Keyword(s):

Cell Cycle ◽

Lung Adenocarcinoma ◽

Positive Feedback ◽

Feedback Loop ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Positive Feedback Loop

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The RASSF1A Tumor Suppressor Restrains Anaphase-Promoting Complex/Cyclosome Activity during the G1/S Phase Transition To Promote Cell Cycle Progression in Human Epithelial Cells

Molecular and Cellular Biology ◽

10.1128/mcb.02291-07 ◽

2008 ◽

Vol 28 (10) ◽

pp. 3190-3197 ◽

Cited By ~ 19

Author(s):

Angelique W. Whitehurst ◽

Rosalyn Ram ◽

Latha Shivakumar ◽

Boning Gao ◽

John D. Minna ◽

...

Keyword(s):

Phase Transition ◽

Cell Cycle ◽

Tumor Suppressor ◽

Epithelial Cells ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

S Phase ◽

Phase Cell ◽

Anaphase Promoting Complex ◽

Cycle Progression

ABSTRACT Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G1/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G1. Surprisingly, we found that RASSF1A is also required to restrict SCFβTrCP activity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G1/S phase cell cycle transition.

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Control of cell cycle progression by phosphorylation of cyclin-dependent kinase (CDK) substrates

Bioscience Reports ◽

10.1042/bsr20090171 ◽

2010 ◽

Vol 30 (4) ◽

pp. 243-255 ◽

Cited By ~ 65

Author(s):

Randy Suryadinata ◽

Martin Sadowski ◽

Boris Sarcevic

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Cell Cycle Progression ◽

Genetic Material ◽

Eukaryotic Cell ◽

S Phase ◽

Cycle Progression ◽

M Phase ◽

Unicellular Organisms ◽

Multicellular Organisms

The eukaryotic cell cycle is a fundamental evolutionarily conserved process that regulates cell division from simple unicellular organisms, such as yeast, through to higher multicellular organisms, such as humans. The cell cycle comprises several phases, including the S-phase (DNA synthesis phase) and M-phase (mitotic phase). During S-phase, the genetic material is replicated, and is then segregated into two identical daughter cells following mitotic M-phase and cytokinesis. The S- and M-phases are separated by two gap phases (G1 and G2) that govern the readiness of cells to enter S- or M-phase. Genetic and biochemical studies demonstrate that cell division in eukaryotes is mediated by CDKs (cyclin-dependent kinases). Active CDKs comprise a protein kinase subunit whose catalytic activity is dependent on association with a regulatory cyclin subunit. Cell-cycle-stage-dependent accumulation and proteolytic degradation of different cyclin subunits regulates their association with CDKs to control different stages of cell division. CDKs promote cell cycle progression by phosphorylating critical downstream substrates to alter their activity. Here, we will review some of the well-characterized CDK substrates to provide mechanistic insights into how these kinases control different stages of cell division.

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NF-κB Function in Growth Control: Regulation of Cyclin D1 Expression and G0/G1-to-S-Phase Transition

Molecular and Cellular Biology ◽

10.1128/mcb.19.4.2690 ◽

1999 ◽

Vol 19 (4) ◽

pp. 2690-2698 ◽

Cited By ~ 551

Author(s):

Michael Hinz ◽

Daniel Krappmann ◽

Alexandra Eichten ◽

Andreas Heder ◽

Claus Scheidereit ◽

...

Keyword(s):

Phase Transition ◽

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Ectopic Expression ◽

Tumor Development ◽

Growth Control ◽

S Phase ◽

Checkpoint Control ◽

Cycle Progression

ABSTRACT Nuclear factor kappa B (NF-κB) has been implicated in the regulation of cell proliferation, transformation, and tumor development. We provide evidence for a direct link between NF-κB activity and cell cycle regulation. NF-κB was found to stimulate transcription of cyclin D1, a key regulator of G1checkpoint control. Two NF-κB binding sites in the human cyclin D1 promoter conferred activation by NF-κB as well as by growth factors. Both levels and kinetics of cyclin D1 expression during G1phase were controlled by NF-κB. Moreover, inhibition of NF-κB caused a pronounced reduction of serum-induced cyclin D1-associated kinase activity and resulted in delayed phosphorylation of the retinoblastoma protein. Furthermore, NF-κB promotes G1-to-S-phase transition in mouse embryonal fibroblasts and in T47D mammary carcinoma cells. Impaired cell cycle progression of T47D cells expressing an NF-κB superrepressor (IκBαΔN) could be rescued by ectopic expression of cyclin D1. Thus, NF-κB contributes to cell cycle progression, and one of its targets might be cyclin D1.

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Ki-67 contributes to normal cell cycle progression and inactive X heterochromatin in p21 checkpoint-proficient human cells

10.1101/134767 ◽

2017 ◽

Author(s):

Xiaoming Sun ◽

Aizhan Bizhanova ◽

Timothy D. Matheson ◽

Jun Yu ◽

Lihua Julie Zhu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Nuclear Lamina ◽

Cell Types ◽

S Phase ◽

Human Cells ◽

Cell Cycle Distribution ◽

Ki 67 ◽

Primary Fibroblast ◽

Cycle Progression

AbstractKi-67 protein is widely used as a tumor proliferation marker. However, whether Ki-67 affects cell cycle progression has been controversial. Here, we demonstrate that depletion of Ki-67 in human hTERT-RPE1, WI-38, IMR90, hTERT-BJ cell lines and primary fibroblast cells slowed entry into S phase and coordinately downregulated genes related to DNA replication. Some gene expression changes were partially relieved in Ki-67-depleted hTERT-RPE1 cells by co-depletion of the Rb checkpoint protein, but more thorough suppression of the transcriptional and cell cycle defects was observed upon depletion of cell cycle inhibitor p21. Notably, induction of p21 upon depletion of Ki-67 was a consistent hallmark of cell types in which transcription and cell cycle distribution were sensitive to Ki-67; these responses were absent in cells that did not induce p21. Furthermore, upon Ki-67 depletion, a subset of inactive × (Xi) chromosomes in female hTERT-RPE1 cells displayed several features of compromised heterochromatin maintenance, including decreased H3K27me3 and H4K20me1 labeling. These chromatin alterations were limited to Xi chromosomes localized away from the nuclear lamina and were not observed in checkpoint-deficient 293T cells. Altogether, our results indicate that Ki-67 integrates normal S phase progression and Xi heterochromatin maintenance in p21 checkpoint-proficient human cells.

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Ki-67 Contributes to Normal Cell Cycle Progression and Inactive X Heterochromatin in p21 Checkpoint-Proficient Human Cells

Molecular and Cellular Biology ◽

10.1128/mcb.00569-16 ◽

2017 ◽

Vol 37 (17) ◽

Cited By ~ 24

Author(s):

Xiaoming Sun ◽

Aizhan Bizhanova ◽

Timothy D. Matheson ◽

Jun Yu ◽

Lihua Julie Zhu ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Nuclear Lamina ◽

Cell Types ◽

S Phase ◽

Human Cells ◽

Cell Cycle Distribution ◽

Ki 67 ◽

Primary Fibroblast ◽

Cycle Progression

ABSTRACT The Ki-67 protein is widely used as a tumor proliferation marker. However, whether Ki-67 affects cell cycle progression has been controversial. Here we demonstrate that depletion of Ki-67 in human hTERT-RPE1, WI-38, IMR90, and hTERT-BJ cell lines and primary fibroblast cells slowed entry into S phase and coordinately downregulated genes related to DNA replication. Some gene expression changes were partially relieved in Ki-67-depleted hTERT-RPE1 cells by codepletion of the Rb checkpoint protein, but more thorough suppression of the transcriptional and cell cycle defects was observed upon depletion of the cell cycle inhibitor p21. Notably, induction of p21 upon depletion of Ki-67 was a consistent hallmark of cell types in which transcription and cell cycle distribution were sensitive to Ki-67; these responses were absent in cells that did not induce p21. Furthermore, upon Ki-67 depletion, a subset of inactive X (Xi) chromosomes in female hTERT-RPE1 cells displayed several features of compromised heterochromatin maintenance, including decreased H3K27me3 and H4K20me1 labeling. These chromatin alterations were limited to Xi chromosomes localized away from the nuclear lamina and were not observed in checkpoint-deficient 293T cells. Altogether, our results indicate that Ki-67 integrates normal S-phase progression and Xi heterochromatin maintenance in p21 checkpoint-proficient human cells.

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