scholarly journals Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins

2010 ◽  
Vol 21 (22) ◽  
pp. 3890-3901 ◽  
Author(s):  
Pankaj Acharya ◽  
Nitin Raj ◽  
Martin S. Buckley ◽  
Liang Zhang ◽  
Stephanie Duperon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activation ◽  
Regulatory Networks ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Point Mutations ◽  
Normal Growth ◽  
Regulatory Pathway ◽  
Protein Motifs ◽  
Related Family

The Retinoblastoma (RB) transcriptional corepressor and related family of pocket proteins play central roles in cell cycle control and development, and the regulatory networks governed by these factors are frequently inactivated during tumorigenesis. During normal growth, these proteins are subject to tight control through at least two mechanisms. First, during cell cycle progression, repressor potential is down-regulated by Cdk-dependent phosphorylation, resulting in repressor dissociation from E2F family transcription factors. Second, RB proteins are subject to proteasome-mediated destruction during development. To better understand the mechanism for RB family protein instability, we characterized Rbf1 turnover in Drosophila and the protein motifs required for its destabilization. We show that specific point mutations in a conserved C-terminal instability element strongly stabilize Rbf1, but strikingly, these mutations also cripple repression activity. Rbf1 is destabilized specifically in actively proliferating tissues of the larva, indicating that controlled degradation of Rbf1 is linked to developmental signals. The positive linkage between Rbf1 activity and its destruction indicates that repressor function is governed in a manner similar to that described by the degron theory of transcriptional activation. Analogous mutations in the mammalian RB family member p107 similarly induce abnormal accumulation, indicating substantial conservation of this regulatory pathway.

scholarly journals CBIO-20. MOLECULAR MECHANISMS OF OLIG2 TRANSCRIPTION FACTOR IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii19-ii20
Author(s):  
Norihiko Saito ◽  
Sho Sato ◽  
Yu Hiramoto ◽  
Satoshi Fujita ◽  
Haruo Nakayama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Regulatory Networks ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Neural Lineage ◽  
Lineage Differentiation ◽  
Neural Stem Progenitor Cells

Abstract Oligodendrocyte lineage transcription factor 2 (OLIG2) promotes proliferation of normal neural stem/progenitor cells and glioma cells. However, the mechanisms underlying the regulation of OLIG2 remain largely unknown. Here, we show that a comprehensive analysis of the critical gene regulatory networks involving OLIG2 in glioma initiating cell (GIC) lines. In vitro differentiation studies showed that proneural GIC lines possess the potential to differentiate into astrocytic, neuronal, and oligodendrocytic lineages, whereas mesenchymal GICs exhibited limited potential for neural lineage differentiation following retinoic acid induction. We also showed that CDK2-mediated OLIG2 phosphorylation stabilizes OLIG2 protein from proteasomal degradation. Phosphorylated OLIG2 binds to the E-Box regions of p27 promoter and represses p27 transcription, which in turn activates CDK2 in positive feedback manner. CDK2-mediated OLIG2 phosphorylation promotes cell cycle progression, cell proliferation, and tumorigenesis. OLIG2 inhibition disrupted cell cycle control mechanism by decreasing CDK2 and elevating apoptosis-related molecules. Inhibition of CDK2 activity disrupted OLIG2-CDK2 interactions and attenuated OLIG2 protein stability.　In addition, OLIG2-high glioma initiating cells are highly sensitive to CDK2 inhibitor treatment, indicating that OLIG2 can be a biomarker for personalized treatment for glioblastoma patients with CDK2 inhibitors. In conclusion, we have identified OLIG2-CDK2 interactions in glioma stem cells that can be targeted by CDK2 inhibitors and this may allow the selection of patients with high likelihood of responding to this therapy.

scholarly journals Regulatory networks integrating cell cycle control with DNA damage checkpoints and double-strand break repair

2011 ◽  
Vol 366 (1584) ◽  
pp. 3562-3571 ◽  
Author(s):  
Petra Langerak ◽  
Paul Russell
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Regulatory Networks ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Strand Break ◽  
Dsb Repair ◽  
Cycle Progression ◽  
Non Homologous End Joining

Double-strand breaks (DSBs), arising from exposure to exogenous clastogens or as a by-product of endogenous cellular metabolism, pose grave threats to genome integrity. DSBs can sever whole chromosomes, leading to chromosomal instability, a hallmark of cancer. Healing broken DNA takes time, and it is therefore essential to temporarily halt cell division while DSB repair is underway. The seminal discovery of cyclin-dependent kinases as master regulators of the cell cycle unleashed a series of studies aimed at defining how the DNA damage response network delays cell division. These efforts culminated with the identification of Cdc25, the protein phosphatase that activates Cdc2/Cdk1, as a critical target of the checkpoint kinase Chk1. However, regulation works both ways, as recent studies have revealed that Cdc2 activity and cell cycle position determine whether DSBs are repaired by non-homologous end-joining or homologous recombination (HR). Central to this regulation are the proteins that initiate the processing of DNA ends for HR repair, Mre11–Rad50–Nbs1 protein complex and Ctp1/Sae2/CtIP, and the checkpoint kinases Tel1/ATM and Rad3/ATR. Here, we review recent findings and provide insight on how proteins that regulate cell cycle progression affect DSB repair, and, conversely how proteins that repair DSBs affect cell cycle progression.

scholarly journals The Prpl  + Gene Required for Pre-mRNA Splicing in Schizosaccharomyces pombe Encodes a Protein That Contains TPR Motifs and Is Similar to Prp6p of Budding Yeast

Genetics ◽  
1997 ◽  
Vol 147 (1) ◽  
pp. 101-115 ◽  
Author(s):  
Seiichi Urushiyama ◽  
Tokio Tani ◽  
Yasumi Ohshima
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
Schizosaccharomyces Pombe ◽  
Protein Interactions ◽  
Nuclear Export ◽  
Cell Cycle Progression ◽  
Synthetic Lethality ◽  
Cell Cycle Control ◽  
Mrna Splicing ◽  
Restrictive Temperature

Abstract The prp (pre-mRNA processing) mutants of the fission yeast Schizosaccharomyces pombe have a defect in pre-mRNA splicing and accumulate mRNA precursors at a restrictive temperature. One of the prp mutants, prp1-4, also has a defect in poly(A)+ RNA transport. The prp1  + gene encodes a protein of 906 amino acid residues that contains 19 repeats of 34 amino acids termed tetratrico peptide repeat (TPR) motifs, which were proposed to mediate protein-protein interactions. The amino acid sequence of Prplp shares 29.6% identity and 50.6% similarity with that of the PRP6 protein of Saccharomyces cerevisiae, which is a component of the U4/U6 snRNP required for spliceosome assembly. No functional complementation was observed between S. pombe prp1  + and S. cerevisiae PRP6. We examined synthetic lethality of prp1-4 with the other known prp mutations in S. pombe. The results suggest that Prp1p interacts either physically or functionally with Prp4p, Prp6p and Prp13p. Interestingly, the prp1  + gene was found to be identical with the zer1  + gene that functions in cell cycle control. These results suggest that Prp1p/Zer1p is either directly or indirectly involved in cell cycle progression and/or poly(A)+ RNA nuclear export, in addition to pre-mRNA splicing.

scholarly journals Bacterial cell cycle control by citrate synthase independent of enzymatic activity

2019 ◽  
Author(s):  
Matthieu Bergé ◽  
Julian Pezzatti ◽  
Víctor González-Ruiz ◽  
Laurence Degeorges ◽  
Serge Rudaz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Citrate Synthase ◽  
Caulobacter Crescentus ◽  
Tricarboxylic Acid Cycle ◽  
Cell Cycle Control ◽  
Tca Cycle ◽  
Cell Cycle Regulators ◽  
Central Metabolism ◽  
Cycle Enzyme

ABSTRACTCoordination of cell cycle progression with central metabolism is fundamental to all cell types and likely underlies differentiation into dispersal cells in bacteria. How central metabolism is monitored to regulate cell cycle functions is poorly understood. A forward genetic selection for cell cycle regulators in the polarized alpha-proteobacterium Caulobacter crescentus unearthed the uncharacterized CitA citrate synthase, a TCA (tricarboxylic acid) cycle enzyme, as unprecedented checkpoint regulator of the G1→S transition. We show that loss of the CitA protein provokes a (p)ppGpp alarmone-dependent G1-phase arrest without apparent metabolic or energy insufficiency. While S-phase entry is still conferred when CitA is rendered catalytically inactive, the paralogous CitB citrate synthase has no overt role other than sustaining TCA cycle activity when CitA is absent. With eukaryotic citrate synthase paralogs known to fulfill regulatory functions, our work extends the moonlighting paradigm to citrate synthase coordinating central (TCA) metabolism with development and perhaps antibiotic tolerance in bacteria.

scholarly journals Activation of the G2/M-Specific Gene CLB2 Requires Multiple Cell Cycle Signals

2007 ◽  
Vol 27 (23) ◽  
pp. 8364-8373 ◽  
Author(s):  
J. Veis ◽  
H. Klug ◽  
M. Koranda ◽  
G. Ammerer
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activation ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Specific Gene ◽  
Histone H4 ◽  
Cycle Progression ◽  
Histone H4 Acetylation ◽  
Multiple Cell

ABSTRACT In budding yeast (Saccharomyces cerevisiae), the periodic expression of the G2/M-specific gene CLB2 depends on a DNA binding complex that mediates its repression during G1 and activation from the S phase to the exit of mitosis. The switch from low to high expression levels depends on the transcriptional activator Ndd1. We show that the inactivation of the Sin3 histone deacetylase complex bypasses the essential role of Ndd1 in cell cycle progression. Sin3 and its catalytic subunit Rpd3 associate with the CLB2 promoter during the G1 phase of the cell cycle. Both proteins dissociate from the promoter at the onset of the S phase and reassociate during G2 phase. Sin3 removal coincides with a transient increase in histone H4 acetylation followed by the expulsion of at least one nucleosome from the promoter region. Whereas the first step depends on Cdc28/Cln1 activity, Ndd1 function is required for the second step. Since the removal of Sin3 is independent of Ndd1 recruitment and Cdc28/Clb activity it represents a unique regulatory step which is distinct from transcriptional activation.

Cdk1-Dependent Phosphorylation ofNPM Overrides G2/M Checkpoint and Increases Leukemic Blasts in Mice

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1322-1322
Author(s):  
Wei Du ◽  
Yun Zhou ◽  
Suzette Pike ◽  
Qishen Pang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Xenograft Model ◽  
Phosphorylation Sites ◽  
M Cell ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Cycle Arrest ◽  
Regulation Of Cell Cycle

Abstract An elevated level of nucleophosmin (NPM) is often found in actively proliferative cells including human tumors. To identify the regulatory role for NPM phosphorylation in proliferation and cell cycle control, a series of mutants targeting the consensus cyclin-dependent kinase (CKD) phosphorylation sites was created to mimic or abrogate either single-site or multi-site phosphorylation. Cells expressing the phosphomimetic NPM mutants showed enhanced proliferation and G2/M cell-cycle transition; whereas nonphosphorylatable mutants induced G2/M cell-cycle arrest. Simultaneous inactivation of two CKD phosphorylation sites at Ser10 and Ser70 (S10A/S70A, NPM-AA) induced phosphorylation of Cdk1 at Tyr15 (Cdc2Tyr15) and increased cytoplasmic accumulation of Cdc25C. Strikingly, stress-induced Cdk1Tyr15 and Cdc25C sequestration were completely suppressed by expression of a double phosphomimetic NPM mutant (S10E/S70E, NPM-EE). Further analysis revealed that phosphorylation of NPM at both Ser10 and Ser70 sites were required for proper interaction between Cdk1 and Cdc25C in mitotic cells. Moreover, the NPM-EE mutant directly bound to Cdc25C and prevented phosphorylation of Cdc25C at Ser216 during mitosis. Finally, NPM-EE overrided stress-induced G2/M arrest, increased peripheral-blood blasts and splenomegaly in a NOD/SCID xenograft model, and promoted leukemia development in Fanconi mouse hematopoietic stem/progenitor cells. Thus, these findings reveal a novel function of NPM on regulation of cell-cycle progression, in which Cdk1-dependent phosphorylation of NPM controls cell-cycle progression at G2/M transition through modulation of Cdc25C activity.

scholarly journals Overexpression of Bcl-w in the Testis Disrupts Spermatogenesis: Revelation of a Role of BCL-W in Male Germ Cell Cycle Control

2003 ◽  
Vol 17 (9) ◽  
pp. 1868-1879 ◽  
Author(s):  
Wei Yan ◽  
Jun-Xing Huang ◽  
Anna-Stina Lax ◽  
Lauri Pelliniemi ◽  
Eeva Salminen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Testicular Development ◽  
Dna Ladder

Abstract To explore physiological roles of BCL-W, a prosurvival member of the BCL-2 protein family, we generated transgenic (TG) mice overexpressing Bcl-w driven by a chicken β-actin promoter. Male Bcl-w TG mice developed normally but were infertile. The adult TG testes displayed disrupted spermatogenesis with various severities ranging from thin seminiferous epithelium containing less germ cells to Sertoli cell-only appearance. No overpopulation of any type of germ cells was observed during testicular development. In contrast, the developing TG testes displayed decreased number of spermatogonia, degeneration, and detachment of spermatocytes and Sertoli cell vacuolization. The proliferative activity of germ cells was significantly reduced during testicular development and spermatogenesis, as determined by in vivo and in vitro 5′-bromo-2′deoxyuridine incorporation assays. Sertoli cells were structurally and functionally normal. The degenerating germ cells were TUNEL-negative and no typical apoptotic DNA ladder was detected. Our data suggest that regulated spatial and temporal expression of BCL-W is required for normal testicular development and spermatogenesis, and overexpression of BCL-W inhibits germ cell cycle entry and/or cell cycle progression leading to disrupted spermatogenesis.

scholarly journals p73 and p63 Sustain Cellular Growth by Transcriptional Activation of Cell Cycle Progression Genes

2009 ◽  
Vol 69 (22) ◽  
pp. 8563-8571 ◽  
Author(s):  
K. Lefkimmiatis ◽  
M. F. Caratozzolo ◽  
P. Merlo ◽  
A. M. D'Erchia ◽  
B. Navarro ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activation ◽  
Cell Cycle Progression ◽  
Cellular Growth ◽  
Cycle Progression

scholarly journals The Retinoblastoma Protein Regulates Pericentric Heterochromatin

2006 ◽  
Vol 26 (9) ◽  
pp. 3659-3671 ◽  
Author(s):  
Christian E. Isaac ◽  
Sarah M. Francis ◽  
Alison L. Martens ◽  
Lisa M. Julian ◽  
Laurie A. Seifried ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromatin Structure ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Pericentric Heterochromatin ◽  
Site Mutation ◽  
Histone Tails ◽  
Binding Cleft ◽  
Heterochromatin Structure

ABSTRACT The retinoblastoma protein (pRb) has been proposed to regulate cell cycle progression in part through its ability to interact with enzymes that modify histone tails and create a repressed chromatin structure. We created a mutation in the murine Rb1 gene that disrupted pRb's ability to interact with these enzymes to determine if it affected cell cycle control. Here, we show that loss of this interaction slows progression through mitosis and causes aneuploidy. Our experiments reveal that while the LXCXE binding site mutation does not disrupt pRb's interaction with the Suv4-20h histone methyltransferases, it dramatically reduces H4-K20 trimethylation in pericentric heterochromatin. Disruption of heterochromatin structure in this chromosomal region leads to centromere fusions, chromosome missegregation, and genomic instability. These results demonstrate the surprising finding that pRb uses the LXCXE binding cleft to control chromatin structure for the regulation of events beyond the G1-to-S-phase transition.

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