scholarly journals Cell Cycle Dysregulation in Oral Cancer

2002 ◽  
Vol 13 (1) ◽  
pp. 51-61 ◽  
Author(s):  
R. Todd ◽  
P.W. Hinds ◽  
K. Munger ◽  
A.K. Rustgi ◽  
O.G. Opitz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Metabolic Stress ◽  
Regulatory Proteins ◽  
Regulatory Pathways ◽  
Oral Cancers ◽  
Molecular Alterations ◽  
Oral Carcinogenesis ◽  
Retinoblastoma Tumor

The dysregulation of the molecular events governing cell cycle control is emerging as a central theme of oral carcinogenesis. Regulatory pathways responding to extracellular signaling or intracellular stress and DNA damage converge on the cell cycle apparatus. Abrogation of mitogenic and anti-mitogenic response regulatory proteins, such as the retinoblastoma tumor suppressor protein (pRB), cyclin D1, cyclin-dependent kinase (CDK) 6, and CDK inhibitors (p21WAF1/CIP1, p27KIP1, and p16INK4a), occur frequently in human oral cancers. Cellular responses to metabolic stress or genomic damage through p53 and related pathways that block cell cycle progression are also altered during oral carcinogenesis. In addition, new pathways and cell cycle regulatory proteins, such as p12DOC-1, are being discovered. The multistep process of oral carcinogenesis likely involves functional alteration of cell cycle regulatory members combined with escape from cellular senescence and apoptotic signaling pathways. Detailing the molecular alterations and understanding the functional consequences of the dysregulation of the cell cycle apparatus in the malignant oral keratinocyte will uncover novel diagnostic and therapeutic approaches.

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.

Cell cycle control by oscillating regulatory proteins inCaulobacter crescentus

BioEssays ◽  
2006 ◽  
Vol 28 (4) ◽  
pp. 355-361 ◽  
Author(s):  
Julia Holtzendorff ◽  
Jens Reinhardt ◽  
Patrick H. Viollier
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
Regulatory Proteins

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 Transcriptional repression and growth suppression by the p107 pocket protein.

1996 ◽  
Vol 16 (7) ◽  
pp. 3606-3614 ◽  
Author(s):  
P Starostik ◽  
K N Chow ◽  
D C Dean
Keyword(s):  
Cell Cycle ◽  
Transcriptional Repression ◽  
Cell Cycle Control ◽  
Transcriptional Repressor ◽  
Growth Suppression ◽  
Suppressor Activity ◽  
Adenovirus E1a ◽  
Cell Growth Suppression ◽  
Retinoblastoma Tumor ◽  
Repressor Activity

p107 is a member of the pocket family of proteins that includes the retinoblastoma tumor suppressor. Overexpression of p107 arrests cells in G1, suggesting that it is important for cell cycle control. This growth suppression is mediated at least in part through the interaction of p107 with a member of the E2F family of cell cycle transcription factors, and this interaction can be disrupted by oncoproteins from DNA tumor viruses such as adenovirus E1a that bind p107. Not only does the binding of p107 to E2F inactivate E2F, but also we show that when p107 is tethered to the promoter through binding to E2F it functions as a general transcriptional repressor. This general repressor activity was also evident when p107 was fused to the DNA binding domain of Gal4 so that it could be directly targeted to the promoter in an E2F-independent fashion. Using p107 mutants, we compared the regions of the protein required for transcriptional repression and cell growth suppression. We found that the pocket domain is sufficient for inactivation of E2F, general repressor activity, and most of the growth suppressor activity. Binding of conserved region 1 from Ela to p107 blocked interaction with E2F, but it did not affect general repressor activity, demonstrating that binding and inactivation of E2F and general repressor activity are distinguishable properties of p107. Within the pocket, two conserved domains, A and B, were sufficient for growth suppression and transcriptional repressor activity. Surprisingly, we found that these two domains were fully functional when they were coexpressed as separate proteins, and we present results suggesting that the domains may interact at the promoter to form an active pocket.

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 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.

scholarly journals The Absence of Caveolin-1 Increases Proliferation and Anchorage- Independent Growth by a Rac-Dependent, Erk-Independent Mechanism

2009 ◽  
Vol 29 (18) ◽  
pp. 5046-5059 ◽  
Author(s):  
Ana Cerezo ◽  
Marta C. Guadamillas ◽  
Jacky G. Goetz ◽  
Sara Sánchez-Perales ◽  
Eric Klein ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Mitogen Activated Protein Kinase ◽  
Serum Starvation ◽  
Regulatory Pathways ◽  
Anchorage Independent Growth ◽  
Caveolin 1 ◽  
Mitogen Activated Protein

ABSTRACT Anchorage-independent growth (AIG) of cancer cells requires escape from integrin-mediated signals. A protein frequently downregulated in cancer, caveolin-1 (Cav1), mediates integrin control of several growth-regulatory pathways. We report that loss of Cav1 results in faster exit from quiescence and progress through the cell cycle, proliferation without anchorage to substrate, and absence of cyclin D1 downregulation upon serum deprivation or detachment. Surprisingly, this proliferative advantage is independent of Erk-mitogen-activated protein kinase signaling; instead, cyclin expression and cell cycle progression in the absence of Cav1 are driven by increased membrane order and Rac targeting. AIG was induced in Cav1-expressing cells by forced membrane targeting of Rac1 or by inhibiting Cav1-mediated internalization of plasma membrane ordered domains at which Rac1 accumulates. Restoring Rho activity, which is downregulated after loss of Cav1, antagonizes Rac1 and prevents cyclin D1 accumulation after serum starvation or loss of adhesion. Anchorage independence and increased proliferation in Cav1-deficient tumoral and null cells are thus due to an increased fraction of active Rac1 at membrane ordered domains. These results provide insight into the mechanisms regulating growth of cancer cells, which frequently lose Cav1 function.

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