scholarly journals Phosphorylation of the RB C-terminus regulates condensin II release from chromatin

2020 ◽  
Author(s):  
Seung J. Kim ◽  
James I. MacDonald ◽  
Frederick A. Dick
Keyword(s):  
Cell Cycle ◽  
Genome Stability ◽  
Cell Cycle Control ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Biologically Relevant ◽  
C Terminus ◽  
Independent Functions ◽  
Phosphorylation Event ◽  
Rb Phosphorylation

ABSTRACTThe retinoblastoma tumour suppressor protein (RB) plays an important role in biological processes such as cell cycle control, DNA damage repair, epigenetic regulation, and genome stability. The canonical model of RB regulation is that cyclin-CDKs phosphorylate, and render RB inactive in late G1/S, promoting entry into S phase. Recently, mono-phosphorylated RB species were described to have distinct cell-cycle independent functions, suggesting that a phosphorylation code dictates diversity of RB function. However, a biologically relevant, functional role of RB phosphorylation at non-CDK sites has remained elusive. Here, we investigated S838/T841 dual phosphorylation, its upstream stimulus, and downstream functional output. We found that mimicking T-cell receptor activation in Jurkat leukemia cells induced sequential activation of downstream kinases including p38 MAPK, and RB S838/T841 phosphorylation. This signaling pathway disrupts RB and condensin II interaction with chromatin. Using cells expressing a WT or S838A/T841A mutant RB fragment, we present evidence that deficiency for this phosphorylation event prevents condensin II release from chromatin.

scholarly journals Phosphorylation of the RB C-terminus regulates condensin II release from chromatin

2020 ◽  
pp. jbc.RA120.016511
Author(s):  
Seung J Kim ◽  
James I MacDonald ◽  
Frederick A. Dick
Keyword(s):  
Cell Cycle ◽  
Genome Stability ◽  
Cell Cycle Control ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Biologically Relevant ◽  
C Terminus ◽  
Independent Functions ◽  
Phosphorylation Event ◽  
Rb Phosphorylation

The retinoblastoma tumour suppressor protein (RB) plays an important role in biological processes such as cell cycle control, DNA damage repair, epigenetic regulation, and genome stability. The canonical model of RB regulation is that cyclin-CDKs phosphorylate, and render RB inactive in late G1/S, promoting entry into S phase. Recently, mono-phosphorylated RB species were described to have distinct cell-cycle independent functions, suggesting that a phosphorylation code dictates diversity of RB function. However, a biologically relevant, functional role of RB phosphorylation at non-CDK sites has remained elusive. Here, we investigated S838/T841 dual phosphorylation, its upstream stimulus, and downstream functional output.  We found that mimicking T-cell receptor activation in Jurkat leukemia cells induced sequential activation of downstream kinases including p38 MAPK, and RB S838/T841 phosphorylation.  This signaling pathway disrupts RB and condensin II interaction with chromatin.  Using cells expressing a WT or S838A/T841A mutant RB fragment, we present evidence that deficiency for this phosphorylation event prevents condensin II release from chromatin.

The Role of Retinoblastoma Protein in Cell Cycle Regulation: An Updated Review

2021 ◽  
Vol 20 ◽  
Author(s):  
Rabih Roufayel ◽  
Rabih Mezher ◽  
Kenneth B. Storey
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Cell Cycle Control ◽  
Expression Of Genes ◽  
E2f Transcription Factor ◽  
Cellular Energetics ◽  
Development And Differentiation ◽  
E2f Transcription Factors ◽  
Rb Phosphorylation

: Selected transcription factors have critical roles to play in organism survival by regulating the expression of genes that control the adaptations needed to handle stress conditions. The retinoblastoma (Rb) protein coupled with the E2F transcription factor family was demonstrated to have roles in controlling the cell cycle during freezing and associated environmental stresses (anoxia, dehydration). Rb phosphorylation or acetylation at different sites provide a mechanism for repressing cell proliferation that is under the control of E2F transcription factors in animals facing stresses that disrupt cellular energetics or cell volume controls. Other central regulators of the cell cycle including Cyclins, Cyclin dependent kinases (Cdks), and checkpoint proteins detect DNA damage or any improper replication, blocking further progression of cell cycle and interrupting cell proliferation. This review provides an insight into the molecular regulatory mechanisms of cell cycle control, focusing on Rb-E2F along with Cyclin-Cdk complexes typically involved in development and differentiation that need to be regulated in order to survive extreme cellular stress.

scholarly journals Cell Cycle Control of Wnt Receptor Activation

2009 ◽  
Vol 17 (6) ◽  
pp. 788-799 ◽  
Author(s):  
Gary Davidson ◽  
Jinlong Shen ◽  
Ya-Lin Huang ◽  
Yi Su ◽  
Emil Karaulanov ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
Receptor Activation

scholarly journals CDK2 activity determines the timing of cell-cycle commitment and sequential DNA replication

2020 ◽  
Author(s):  
Sungsoo Kim ◽  
Alessandra Leong ◽  
Chellam Nayar ◽  
Minah Kim ◽  
Hee Won Yang
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Mammalian Cells ◽  
Genome Stability ◽  
Threshold Level ◽  
Cyclin Dependent Kinases ◽  
Safety Mechanism ◽  
Cdk2 Activity ◽  
Tightly Coupled ◽  
Rb Phosphorylation

AbstractTo enter the cell cycle, mammalian cells must cross a point of no return (the commitment point), after which they proceed through the cell cycle regardless of changes in external signaling. This process is tightly regulated by the cyclin-dependent kinases (CDKs) and downstream molecules such as retinoblastoma (Rb). Here we show that CDK2 activity coordinates the timing of cell-cycle commitment and DNA replication. CDK4/6 activation initiates Rb phosphorylation and E2F activity, causing a gradual increase in CDK2 activity. Once CDK2 activity reaches a threshold level, CDK2 triggers the commitment point by maintaining Rb phosphorylation and subsequently initiates DNA replication. While the timing of the commitment point is tightly coupled with DNA replication, our experiments, which acutely increased CDK2 activity, suggest that the timing of the commitment point is before DNA replication. These findings highlight how cells utilize a safety mechanism to maintain genome stability by protecting against incomplete DNA replication.

scholarly journals Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27Kip1 degradation

2005 ◽  
Vol 202 (1) ◽  
pp. 157-168 ◽  
Author(s):  
Leonor M. Sarmento ◽  
Hui Huang ◽  
Ana Limon ◽  
William Gordon ◽  
Jacquenilson Fernandes ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Adult Stem Cells ◽  
Kinase Inhibitors ◽  
Cell Cycle Control ◽  
Receptor Activation ◽  
S Phase ◽  
Notch Receptor ◽  
Cell Surface Receptor ◽  
Surface Receptor

Cyclin-dependent kinase inhibitors (CKIs) and Notch receptor activation have been shown to influence adult stem cells and progenitors by altering stem cell self-renewal and proliferation. Yet, no interaction between these molecular pathways has been defined. Here we show that ligand-independent and ligand-dependent activation of Notch1 induces transcription of the S phase kinase–associated protein 2 (SKP2), the F-box subunit of the ubiquitin-ligase complex SCFSKP2 that targets proteins for degradation. Up-regulation of SKP2 by Notch signaling enhances proteasome-mediated degradation of the CKIs, p27Kip1 and p21Cip1, and causes premature entry into S phase. Silencing of SKP2 by RNA interference in G1 stabilizes p27Kip1 and p21Cip1 and abolishes Notch effect on G1-S progression. Thus, SKP2 serves to link Notch1 activation with the cell cycle machinery. This novel pathway involving Notch/SKP2/CKIs connects a cell surface receptor with proximate mediators of cell cycle activity, and suggests a mechanism by which a known physiologic mediator of cell fate determination interfaces with cell cycle control.

scholarly journals Loss of Rereplication Control in Saccharomyces cerevisiae Results in Extensive DNA Damage

2005 ◽  
Vol 16 (1) ◽  
pp. 421-432 ◽  
Author(s):  
Brian M. Green ◽  
Joachim J. Li
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Dna Damage ◽  
Genome Stability ◽  
Eukaryotic Cell ◽  
Entire Genome ◽  
Yeast Saccharomyces Cerevisiae ◽  
Checkpoint Response ◽  
Checkpoint Protein ◽  
C Terminus

To maintain genome stability, the entire genome of a eukaryotic cell must be replicated once and only once per cell cycle. In many organisms, multiple overlapping mechanisms block rereplication, but the consequences of deregulating these mechanisms are poorly understood. Here, we show that disrupting these controls in the budding yeast Saccharomyces cerevisiae rapidly blocks cell proliferation. Rereplicating cells activate the classical DNA damage-induced checkpoint response, which depends on the BRCA1 C-terminus checkpoint protein Rad9. In contrast, Mrc1, a checkpoint protein required for recognition of replication stress, does not play a role in the response to rereplication. Strikingly, rereplicating cells accumulate subchromosomal DNA breakage products. These rapid and severe consequences suggest that even limited and sporadic rereplication could threaten the genome with significant damage. Hence, even subtle disruptions in the cell cycle regulation of DNA replication may predispose cells to the genomic instability associated with tumorigenesis.

scholarly journals BRCTx Is a Novel, Highly Conserved RAD18-Interacting Protein

2005 ◽  
Vol 25 (2) ◽  
pp. 779-788 ◽  
Author(s):  
David J. Adams ◽  
Louise van der Weyden ◽  
Fanni V. Gergely ◽  
Mark J. Arends ◽  
Bee Ling Ng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
Similar Rate ◽  
Targeted Mutagenesis ◽  
Brct Domain ◽  
Wild Type ◽  
Interacting Protein ◽  
Dna Damaging Agents ◽  
C Terminus ◽  
Knockout Animals

ABSTRACT The BRCT domain is a highly conserved module found in many proteins that participate in DNA damage checkpoint regulation, DNA repair, and cell cycle control. Here we describe the cloning, characterization, and targeted mutagenesis of Brctx, a novel gene with a BRCT motif. Brctx was found to be expressed ubiquitously in adult tissues and during development, with the highest levels found in testis. Brctx-deficient mice develop normally, show no pathological abnormalities, and are fertile. BRCTx binds to the C terminus of hRAD18 in yeast two-hybrid and immunoprecipitation assays and colocalizes with this protein in the nucleus. Despite this, Brctx-deficient murine embryonic fibroblasts (MEFs) do not show overt sensitivity to DNA-damaging agents. MEFs from Brctx-deficient embryos grow at a similar rate to wild-type MEF CD4/CD8 expressions, and the cell cycle parameters of thymocytes from wild-type and Brctx knockout animals are indistinguishable. Intriguingly, the BRCT domain of BRCTx is responsible for mediating its localization to the nucleus and centrosome in interphase cells. We conclude that, although highly conserved, Brctx is not essential for the above-mentioned processes and may be redundant.

scholarly journals T Cell Receptor-induced Activation and Apoptosis In Cycling Human T Cells Occur throughout the Cell Cycle

1999 ◽  
Vol 10 (12) ◽  
pp. 4441-4450 ◽  
Author(s):  
Michael Karas ◽  
Tal Z. Zaks ◽  
Liu JL ◽  
Derek LeRoith
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
Fas Ligand ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Activation Induced Cell Death ◽  
Human T Cells

Previous studies have found conflicting associations between susceptibility to activation-induced cell death and the cell cycle in T cells. However, most of the studies used potentially toxic pharmacological agents for cell cycle synchronization. A panel of human melanoma tumor-reactive T cell lines, a CD8+ HER-2/neu-reactive T cell clone, and the leukemic T cell line Jurkat were separated by centrifugal elutriation. Fractions enriched for the G0–G1, S, and G2–M phases of the cell cycle were assayed for T cell receptor-mediated activation as measured by intracellular Ca2+flux, cytolytic recognition of tumor targets, and induction of Fas ligand mRNA. Susceptibility to apoptosis induced by recombinant Fas ligand and activation-induced cell death were also studied. None of the parameters studied was specific to a certain phase of the cell cycle, leading us to conclude that in nontransformed human T cells, both activation and apoptosis through T cell receptor activation can occur in all phases of the cell cycle.

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