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hallmarks_of_cancer

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701

22705496_0

DNA double-strand breaks ( DSBs ) in embryonic stem ( ES ) cells are repaired primarily by homologous recombination ( HR ) .

702

22705496_1

The mechanism by which HR is regulated in these cells , however , remains enigmatic .

703

22705496_2

To gain insight into such regulatory mechanisms , we have asked how protein levels of Rad51 , a key component of HR , are controlled in mouse ES cells and mouse embryo fibroblasts ( MEFs ) .

704

22705496_3

The Rad51 protein level is about 15-fold higher in ES cells than in MEFs .

705

22705496_4

The level of Rad51 mRNA , however , is only higher , indicating that the differences in mRNA levels due to rates of transcription or mRNA stability are not sufficient to account for the large difference in the abundance of Rad51 protein .

706

22705496_5

Comparison of Rad51 half-lives between ES cells and MEFs also did not explain the elevated level of Rad51 protein in the ES cells .

707

22705496_6

A comparative assessment of the Rad51 translation level demonstrated that it is translated with much greater efficacy in ES cells than in MEFs .

708

22705496_7

To determine whether this high level of translation in ES cells is a general phenomenon in these cells or whether it is a characteristic of specific proteins , such as those involved with recombination and cell cycle progression , we compared mechanisms that regulate the level of Pcna in ES cells with those that regulate Rad51 .

709

22705496_8

The half-life of Pcna and its rate of synthesis were considerably different from those of Rad51 in ES cells , demonstrating that regulation of Rad51 abundance cannot be generalized to other ES cell proteins and not to proteins involved in DNA replication and cell cycle control .

710

22705496_9

Finally , we show that only a small proportion of the abundant Rad51 protein population is activated under basal conditions in ES cells and recruited to DNA DSBs and/or stalled replication forks .

711

22891289_0

MDSCs and Tregs play an essential role in the immunosuppressive networks that contribute to tumor-immune evasion .

712

22891289_1

The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-talk between MDSC and Treg remain incompletely defined .

713

22891289_2

Previous reports have suggested that MDSC may contribute to Treg induction in cancer .

714

22891289_3

Herein , we provide evidence that tumor-induced gr-MDSCs , endowed with the potential of suppressing conventional T Lc , surprisingly impair TGF-β1-mediated generation of CD4(+)CD25(+)FoxP3(+) iTregs .

715

22891289_4

Furthermore , gr-MDSCs impede the proliferation of nTregs without , however , affecting FoxP3 expression .

716

22891289_5

Suppression of iTreg differentiation from na�ve CD4(+) cells by gr-MDSC occurs early in the polarization process , requires inhibition of early T cell activation , and depends on ROS and IDO but does not require arginase 1 , iNOS , NO , cystine/cysteine depletion , PD-1 and PD-L1 signaling , or COX-2 .

717

22891289_6

These findings thus indicate that gr-MDSCs from TB hosts have the unanticipated ability to restrict immunosuppressive Tregs .

718

1582420_0

Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer .

719

1582420_1

Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination , we have measured telomere length , telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5 .

720

1582420_2

In all mortal populations , telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures .

721

1582420_3

When transformed cells reached crisis , the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed .

722

1582420_4

In immortal cells , telomere length and frequency of dicentric chromosomes stabilized after crisis .

723

1582420_5

Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations .

724

1582420_6

These results suggest that chromosomes with short ( TTAGGG)n tracts are recombinogenic , critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization .

725

20954073_0

Ceramide induces cell cycle arrest and apoptotic cell death associated with increased levels of p27(kip1) .

726

20954073_1

The aim of this study was to examine the effects of ceramide on p27(kip1) protein levels as a measure of cell cycle arrest and apoptosis .

727

20954073_2

Results showed that ceramide increased p27(kip1) protein levels through activation of protein phosphatase 2A ( PP2A ) in PC-3 prostate cancer cells .

728

20954073_3

Treatment of cells with the PP2A inhibitor okadaic acid or with PP2A-Cα siRNA inhibited ceramide-induced enhanced p27(kip1) protein expression and Akt dephosphorylation , and prevented Skp2 downregulation .

729

20954073_4

Overexpression of constitutively active Akt attenuated ceramide-induced Skp2 downregulation and p27(kip1) upregulation .

730

20954073_5

In addition , ceramide stimulated binding of the PP2A catalytic subunit PP2A-Cαβ to Akt as assessed by immunoprecipitation experiments , indicating that PP2A is involved in the induction of p27(kip1) via inhibition of Akt pathway .

731

20954073_6

Finally , whether PP2A can regulate p27(kip1) expression independently of Akt pathway was determined .

732

20954073_7

Knockdown of PP2A-Cα with siRNA reduced p27(kip1) levels in the presence of Akt inhibitor .

733

20954073_8

These data reveal that PP2A is a regulator of ceramide-induced p27(kip1) expression via Akt-dependent and Akt-independent pathways .

734

20217555_0

Tumor invasion and metastasis are the primary causes of cancer patient mortality , underscoring the need for identification of novel genes and signaling pathways that mediate these prognosis-determining phenomena .

735

20217555_1

To identify and characterize novel lung adenocarcinoma genes associated with lung cancer progression , we created a bioinformatics-based approach that focuses on human cell-cycle-regulated genes that have evolved only in higher organisms but not in lower eukaryotic cells .

736

20217555_2

In siRNA experiments in lung cancer cells , FLJ10540 was identified as one of several novel targets involved in cell migration and invasion .

737

20217555_3

Here , we demonstrate that PI3K inhibition affects FLJ10540-mediated cell migration and invasion and further , that FLJ10540 knockdown ablates AKT-Ser(473) phosphorylation .

738

20217555_4

Taken together , these findings indicate that the FLJ10540/PI3K/AKT pathway may harbor new therapeutic targets for treating invasive lung adenocarcinoma .

739

12554766_0

Steroid hormone receptors , including estrogen receptor-alpha ( ERalpha ) , are ligand-activated transcription factors , and hormone binding leads to depletion of receptor levels via preteasome-mediated degradation .

740

12554766_1

NEDD8 ( neural precursor cell-expressed developmentally down-regulated ) is an ubiquitin-like protein essential for protein processing and cell cycle progression .

741

12554766_2

We recently demonstrated that ubiquitin-activating enzyme ( Uba)3 , the catalytic subunit of the NEDD8-activating enzyme , inhibits ERalpha transcriptional activity .

742

12554766_3

Here we report that Uba3-mediated inhibition of ERalpha transactivation function is due to increased receptor protein turnover .

743

12554766_4

Coexpression of Uba3 with ERalpha increased receptor degradation by the 26S proteasome .

744

12554766_5

Inhibition of NEDD8 activation and conjugation diminished polyubiquitination of ERalpha and blocked proteasome-mediated degradation of receptor protein .

745

12554766_6

The antiestrogen ICI 182,780 is known to induce ER degradation .

746

12554766_7

In human MCF7 breast cancer cells modified to contain a disrupted NEDD8 pathway , ICI 182,780 degradation of ERalpha was impaired , and the antiestrogen was ineffective at inhibiting cell proliferation .

747

12554766_8

This study provides the first evidence linking nuclear receptor degradation with the NEDD8 pathway and the ubiquitin-proteasome system , suggesting that the two pathways can act together to modulate ERalpha turnover and cellular responses to estrogens .

748

12554766_9

Based on our observation that an intact NEDD8 pathway is essential for the antiproliferation activity of the ICI 182,780 in ERalpha positive breast cancer cells , we propose that disruptions in the NEDD8 pathway provide a mechanism by which breast cancer cells acquire antiestrogen resistance while retaining expression of ERalpha .

749

23263278_0

The mechanisms by which tumour cells metastasize and the role that cell polarity proteins play in this process are not well understood .

750

23263278_1

We report that partitioning defective protein 3 ( Par3 ) is dysregulated in metastasis in human breast cancer , and is associated with a higher tumour grade and ErbB2-positive status .

751

23263278_2

Downregulation of Par3 cooperated with ErbB2 to induce cell invasion and metastasis in vivo .

752

23263278_3

Interestingly , the metastatic behaviour was not associated with an overt mesenchymal phenotype .

753

23263278_4

However , loss of Par3 inhibited E-cadherin junction stability , disrupted membrane and actin dynamics at cell-cell junctions and decreased cell-cell cohesion in a manner dependent on the Tiam1/Rac-GTP pathway .

754

23263278_5

Inhibition of this pathway restored E-cadherin junction stability and blocked invasive behaviour of cells lacking Par3 , suggesting that loss of Par3 promotes metastatic behaviour of ErbB2-induced tumour epithelial cells by decreasing cell-cell cohesion .

755

24142698_0

Pyruvate kinase M2 ( PKM2 ) is a key player in the Warburg effect of cancer cells .

756

24142698_1

However , the mechanisms of regulating PKM2 are not fully elucidated .

757

24142698_2

Here , we identified the protein-serine/threonine kinase PIM2 , a known oncogene , as a novel binding partner of PKM2 .

758

24142698_3

The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells .

759

24142698_4

Importantly , we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue , resulting in an increase of PKM2 protein levels .

760

24142698_5

Compared with wild type , PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis , co-activating HIF-1\u03b1 and \u03b2-catenin , and cell proliferation , while enhancing mitochondrial respiration of cancer cells .

761

24142698_6

These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer , highlighting PIM2 as a potential therapeutic target .

762

22351035_0

Approximately 50% of human tumors have a mutation in TP53 .

763

22351035_1

The pattern and spectra of TP53 mutations often differ between cancer types , perhaps due to different etiological factors .

764

22351035_2

The Hupki ( human TP53 knock-in ) mouse embryo fibroblast ( HUF ) immortalization assay is useful for studying mutagenesis in the human TP53 gene by environmental carcinogens .

765

22351035_3

Prior to initiating an immortalization assay , carcinogen treatment conditions must be optimized , which can require a large number of cells .

766

22351035_4

As primary HUF cultures senesce within 2 weeks , restricting their use , we investigated whether immortalized HUFs retaining wild-type TP53 can be surrogates for primary HUFs in initial treatment optimization .

767

22351035_5

DNA damage by eight compounds found in diesel exhaust , benzo[a]pyrene , 3-nitrobenzanthrone , 1-nitropyrene , 1,3-dinitropyrene , 1,6-dinitropyrene , 1,8-dinitropyrene , 6-nitrochrysene , and 3-nitrofluorene , was assessed by ( 32 ) P-postlabeling and the alkaline comet assay in primary HUFs and in an immortal HUF cell line J201 .

768

22351035_6

For most compounds , higher levels of DNA adducts accumulated in J201 cells than in primary HUFs .

769

22351035_7

This difference was not reflected in the comet assay or by cell viability changes .

770

22351035_8

Experiments in three additional immortal HUF cell lines ( AAI49 , U56 , and E2-143 ) confirmed strong differences in DNA adduct levels compared with primary HUFs .

771

22351035_9

However , these did not correlate with the protein expression of Nqo1 or Nat1/2 , or with gene expression of Cyp1a1 or Cyp1b1 .

772

22351035_10

Our results show that using immortal HUFs as surrogates for primary HUFs in genotoxicity screening has limitations and that DNA adduct formation is the best measure of genotoxicity of the nitro-polycyclic aromatic hydrocarbons tested in HUFs .

773

21152038_0

SWAP-70 , a phosphatidylinositol trisphosphate ( PtdIns(3,4,5)P(3) ) binding protein , has been suggested to be involved in transformation of mouse embryo fibroblasts ( MEFs ) as well as membrane ruffling after growth factor stimulation of the cells .

774

21152038_1

A mutant , SWAP-70-374 , was found to be able to bind to F-actin in vitro , whereas wild-type SWAP-70 failed to do so .

775

21152038_2

This mutant was present at the plasma membrane without any stimulation while the wild-type protein was present only in the cytosol unless cells were stimulated with EGF .

776

21152038_3

Expression of this mutant in MEFs resulted in morphologic transformation , fast growth , and loss of contact inhibition , suggesting that SWAP-70 with this mutation can transform the cells .

777

21152038_4

ERK1/2 was activated in SWAP-70-374-transformed cells .

778

21152038_5

Use of MEK inhibitors revealed that the ERK1/2 pathway does not affect the cell growth of MEFs but is responsible for loss of contact inhibition .

779

21152038_6

To investigate the function of SWAP-70 further , drugs that can inhibit SWAP-70-dependent cell responses were screened .

780

21152038_7

Among various drugs , sanguinarine was found to inhibit transformation of MEFs by SWAP-70-374 .

781

21152038_8

This drug was able to inhibit SWAP-70-mediated membrane ruffling as well , suggesting that its effect was closely related to the SWAP-70 signaling pathway .

782

21152038_9

These results suggest that SWAP-70-374 can activate some signaling pathways , including the ERK1/2 pathway , to transform MEFs .

783

21178304_0

Extensive biochemical and structural analyses have been performed on the putative DNA repair proteins of hyperthermophilic archaea , in contrast to the few genetic analyses of the genes encoding these proteins .

784

21178304_1

Accordingly , little is known about the repair pathways used by archaeal cells at high temperature .

785

21178304_2

Here , we attempted to disrupt the genes encoding the potential repair proteins in the genome of the hyperthermophilic archaeon Thermococcus kodakaraensis .

786

21178304_3

We succeeded in isolating null mutants of the hjc , hef , hjm , xpb , and xpd genes , but not the radA , rad50 , mre11 , herA , nurA , and xpg/fen1 genes .

787

21178304_4

Phenotypic analyses of the gene-disrupted strains showed that the xpb and xpd null mutants are only slightly sensitive to ultraviolet ( UV ) irradiation , methyl methanesulfonate ( MMS ) and mitomycin C ( MMC ) , as compared with the wild-type strain .

788

21178304_5

The hjm null mutant showed sensitivity specifically to mitomycin C. On the other hand , the null mutants of the hjc gene lacked increasing sensitivity to any type of DNA damage .

789

21178304_6

The Hef protein is particularly important for maintaining genome homeostasis , by functioning in the repair of a wide variety of DNA damage in T. kodakaraensis cells .

790

21178304_7

Deletion of the entire hef gene or of the segments encoding either its nuclease or helicase domain produced similar phenotypes .

791

21178304_8

The high sensitivity of the Δhef mutants to MMC suggests that Hef performs a critical function in the repair process of DNA interstrand cross-links .

792

21178304_9

These damage-sensitivity profiles suggest that the archaeal DNA repair system has processes depending on repair-related proteins different from those of eukaryotic and bacterial DNA repair systems using homologous repair proteins analyzed here .

793

1491701_0

PRL induces quiescent Nb2 rat T-lymphoma cells to undergo mitogenesis .

794

1491701_1

Upon PRL stimulation , the transcription factor interferon regulatory factor-1 ( IRF-1 ) is induced as a novel T-cell activation gene in Nb2 cells .

795

1491701_2

Surprisingly , IRF-1 is expressed twice during a single PRL-induced growth cycle : first during the early G1 phase , in an immediate transient peak from 15 min to 2 h , and second during the G1/S phase transition , in a broader peak beginning at 8 h .

796

1491701_3

The unusual biphasic expression of IRF-1 mRNA is accompanied both times by de novo IRF-1 protein synthesis .

797

1491701_4

However , the rate of IRF-1 protein turnover appears to be different in G1 and S phases .

798

1491701_5

IRF-1 protein expressed in G1 exhibits a half-life of about 25 min , whereas in the S phase , the half-life is about 60 min .

799

1491701_6

By washing out PRL at various times during G1 , we found a direct correlation among the length of PRL exposure , the second peak of IRF-1 mRNA expression , and DNA synthesis .

800

1491701_7

Our data suggest that PRL and one putative nuclear mediator , IRF-1 , may be important in two distinct phases of the cell cycle : first in cell cycle activation , and then in S phase progression .