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PubMed1997

Alterations in the catalytic activity of yeast DNA topoisomerase I result in cell cycle arrest and cell death.

Eukaryotic DNA topoisomerase I catalyzes the relaxation of supercoiled DNA through a concerted mechanism of DNA strand breakage and religation. The cytotoxic activity of camptothecin results from the reversible stabilization of a covalent enzyme-DNA intermediate. Mutations in two conserved regions of yeast DNA topoisomerase I induced a similar mechanism of cell killing, albeit through different effects on enzyme catalysis. In Top1T722Ap, substituting Ala for Thr722 reduced enzyme specific activity by 3-fold, yet enhanced the stability of the covalent enzyme-DNA complex. In contrast, Top1R517Gp was 1,000-fold less active and camptothecin resistant. Nevertheless, salt-stable DNA-enzyme intermediates were detected. Mutation of the active-site tyrosine abrogated mutant enzyme activity and cytotoxicity, while sublethal levels of top1T722A expression increased rDNA recombination. In checkpoint proficient cells, pGAL1-induced top1 expression coincided with the accumulation of a terminal G2-arrested phenotype. Although the acquisition of this phenotype did not require Rad9p, Top1R517Gp- and Top1T722Ap-induced lethality was enhanced in rad9Delta strains. Thus, despite mechanistic differences between Top1R517Gp and Top1T722Ap, the DNA lesions resulting from the enhanced stability of the covalent enzyme-DNA intermediates were sufficient to cause cell cycle arrest and cell death.

Apoptosis↗

PubMed2004

Acanthamoeba induces cell-cycle arrest in host cells.

Acanthamoeba can cause fatal granulomatous amoebic encephalitis (GAE) and eye keratitis. However, the pathogenesis and pathophysiology of these emerging diseases remain unclear. In this study, the effects of Acanthamoeba on the host cell cycle using human brain microvascular endothelial cells (HBMEC) and human corneal epithelial cells (HCEC) were determined. Two isolates of Acanthamoeba belonging to the T1 genotype (GAE isolate) and T4 genotype (keratitis isolate) were used, which showed severe cytotoxicity on HBMEC and HCEC, respectively. No tissue specificity was observed in their ability to exhibit binding to the host cells. To determine the effects of Acanthamoeba on the host cell cycle, a cell-cycle-specific gene array was used. This screened for 96 genes specific for host cell-cycle regulation. It was observed that Acanthamoeba inhibited expression of genes encoding cyclins F and G1 and cyclin-dependent kinase 6, which are proteins important for cell-cycle progression. Moreover, upregulation was observed of the expression of genes such as GADD45A and p130 Rb, associated with cell-cycle arrest, indicating cell-cycle inhibition. Next, the effect of Acanthamoeba on retinoblastoma protein (pRb) phosphorylation was determined. pRb is a potent inhibitor of G1-to-S cell-cycle progression; however, its function is inhibited upon phosphorylation, allowing progression into S phase. Western blotting revealed that Acanthamoeba abolished pRb phosphorylation leading to cell-cycle arrest at the G1-to-S transition. Taken together, these studies demonstrated for the first time that Acanthamoeba inhibits the host cell cycle at the transcriptional level, as well as by modulating pRb phosphorylation using host cell-signalling mechanisms. A complete understanding of Acanthamoeba-host cell interactions may help in developing novel strategies to treat Acanthamoeba infections.

Acanthamoeba↗

PubMed1998

Levels of p53 in Epstein-Barr virus-infected cells determine cell fate: apoptosis, cell cycle arrest at the G1/S boundary without apoptosis, cell cycle arrest at the G2/M boundary without apoptosis, or unrestricted proliferation.

The marked increases in p53 and p21/WAF1 levels that occur during Epstein-Barr virus (EBV) infection and the generation of immortal B lymphoblastoid cell lines (LCL) do not lead to growth arrest or apoptosis, although increasing wild-type (wt) p53 levels in EBV-infected cells by transfection or DNA damage induce these effects. We hypothesized that the concentration of p53 relative to that of LMP1 determines whether EBV-infected B cells undergo growth arrest and apoptosis. Cell cycle arrest and apoptosis were evaluated in LCL expressing varying p53 levels achieved by treating the cells with increasing concentrations of cisplatin, and we supplemented this approach with experiments in EBV-infected Burkitt's lymphoma (BL) cells transfected with a temperature-sensitive (ts) mutant human p53 and studies in LCL infected with recombinant adenoviruses expressing wt and ts mutant p53. Small increases in p53 and p21/WAF1 led to cell cycle arrest at the G2/M boundary, but not to apoptosis; moderate increases resulted in growth arrest at the G1/S boundary, also without apoptosis; and large increases also induced apoptosis. These results confirm the hypothesis and reveal unanticipated complexities in cell cycle regulation by p53.

Apoptosis↗

PubMed1999

Overexpression of D-type cyclins, E2F-1, SV40 large T antigen and HPV16 E7 rescue cell cycle arrest of tsBN462 cells caused by the CCG1/TAF(II)250 mutation.

tsBN462 cells, which have a point mutation in CCG1/TAF(II)250, a component of TFIID complex, arrest in G1 at the nonpermissive temperature of 39.5 degrees C. Overexpression of D-type cyclins rescued the cell cycle arrest of tsBN462 cells, suggesting that the cell cycle arrest was through Rb. Consistent with this, overexpression of E2F-1, whose function is repressed by the hypophosphorylated form of Rb, also rescued the cell cycle arrest. Moreover, expression of the viral oncoproteins SV40 large T antigen and HPV16 E7, which both bind Rb and inactivate its function, rescued the cell cycle arrest, whereas HPV16 E6 did not. Mutation of the Rb-binding motif in E7 abrogated its ability to rescue the cell cycle arrest. Expression of exogenous cyclin D1, SV40 large T antigen or CCG1/TAF(II)250 increased cyclin A expression at 39.5 degrees C. Coexpression of HPV16 E7 and adenovirus E1b19K, which blocks apoptosis, rescued the proliferation of tsBN462 cells at 38.5 degrees C. To investigate the mechanism underlying the lack of cyclin D1 expression, deletion analysis of cyclin D1 promoter was performed. The 0.15 kbp cyclin D1 core promoter region, which lacks any transcription factor binding motifs, still exhibited a temperature-sensitive phenotype in tsBN462 cells suggesting that CCG1/TAF(II)250 is critical for the function of the cyclin D1 core promoter.

Animals↗

PubMed1996

Hydroxyurea induces recombination in dividing but not in G1 or G2 cell cycle arrested yeast cells.

Hydroxyurea, a chemotherapeutic and radiosensitizing agent, inhibits ribonucleotide reductase, arrests cells in the S-phase and is mutagenic and recombinagenic. In this paper we investigated whether the recombinagenic activity of hydroxyurea is due to the same activity that leads to arrest in the S-phase or to a more direct action on DNA. The effect of hydroxyurea on intrachromosomal and interchromosomal recombination was investigated in dividing and in G1 or G2 cell cycle-arrested cells of the yeast Saccharomyces cerevisiae. Treatment of dividing cells with hydroxyurea resulted in a large increase in recombination frequencies, even at low non-toxic doses. In contrast, in cells arrested in the G1 or G2 phase, hydroxyurea failed to induce recombination, even at 60-fold higher toxic doses. The presence of metabolic activation (S9 mix) did not change the effects of hydroxyurea on recombination. The data suggest that the recombinagenic activity of hydroxyurea may not be due to any direct effect of hydroxyurea on DNA, but may be linked to the inhibition of ribonucleotide reductase causing inhibition of DNA synthesis leading to S-phase arrest and possibly causing recombinagenic lesions.

Antineoplastic Agents↗

PubMed1999

Polyamine depletion arrests cell cycle and induces inhibitors p21(Waf1/Cip1), p27(Kip1), and p53 in IEC-6 cells.

The polyamines spermidine and spermine and their precursor putrescine are intimately involved in and are required for cell growth and proliferation. This study examines the mechanism by which polyamines modulate cell growth, cell cycle progression, and signal transduction cascades. IEC-6 cells were grown in the presence or absence of DL-alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, which is the first rate-limiting enzyme for polyamine synthesis. Depletion of polyamines inhibited growth and arrested cells in the G1 phase of the cell cycle. Cell cycle arrest was accompanied by an increase in the level of p53 protein and other cell cycle inhibitors, including p21(Waf1/Cip1) and p27(Kip1). Induction of cell cycle inhibitors and p53 did not induce apoptosis in IEC-6 cells, unlike many other cell lines. Although polyamine depletion decreased the expression of extracellular signal-regulated kinase (ERK)-2 protein, a sustained increase in ERK-2 isoform activity was observed. The ERK-1 protein level did not change, but ERK-1 activity was increased in polyamine-depleted cells. In addition, polyamine depletion induced the stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK) type of mitogen-activated protein kinase (MAPK). Activation of JNK-1 was the earliest event; within 5 h after DFMO treatment, JNK activity was increased by 150%. The above results indicate that polyamine depletion causes cell cycle arrest and upregulates cell cycle inhibitors and suggest that MAPK and JNK may be involved in the regulation of the activity of these molecules.

Animals↗

PubMed1999

Vitamin K3 induces cell cycle arrest and cell death by inhibiting Cdc25 phosphatase.

Our early reports have indicated that vitamin K3 (VK3) exerts antitumour activity by inhibiting Cdk1 activity and overexpressing the c-myc gene to induce an apoptotic cell death. In the present study, we investigated the effect of VK3 on Cdc25 phosphatase, a Cdk1 activator and c-Myc-downstream protein. Increased protein level but decreased activity of Cdc25A phosphatase was found in cervical carcinoma SiHa cells treated with VK3 for 1 h and allowed to recover for 8, 24, 30 or 45 h. The binding of VK3 to Cdc25 phosphatase was proven by incubating [methyl-3H]-VK3 with the 27 kDa-catalytic domain of Cdc25A phosphatase at 35 degrees C for 2 h. We found that VK3 inhibited cyclin E expression at late G1 phase and cyclin A at G1/S transition of the aphidicolin-synchronised SiHa cells, but had no effect on Cdk2 and Cdk4. The inhibition of cyclins E and A expression was associated with cell cycle progression delay in the S phase. These results indicate that binding of VK3 to the catalytic domain of Cdc25 phosphatase results in the formation of inactive, hyperphosphorylated Cdk1 that subsequently induces cell cycle arrest, leading to cell death. These findings suggest a possible therapeutic strategy, with VK3 serving as a potential antagonist to tumours expressing high levels of proteins containing cysteine such as oncogenic Cdc25A phosphatase.

Apoptosis↗

PubMed2005

Tubulin cofactor A gene silencing in mammalian cells induces changes in microtubule cytoskeleton, cell cycle arrest and cell death.

Microtubules are polymers of alpha/beta-tubulin participating in essential cell functions. A multistep process involving distinct molecular chaperones and cofactors produces new tubulin heterodimers competent to polymerise. In vitro cofactor A (TBCA) interacts with beta-tubulin in a quasi-native state behaving as a molecular chaperone. We have used siRNA to silence TBCA expression in HeLa and MCF-7 mammalian cell lines. TBCA is essential for cell viability and its knockdown produces a decrease in the amount of soluble tubulin, modifications in microtubules and G1 cell cycle arrest. In MCF-7 cells, cell death was preceded by a change in cell shape resembling differentiation.

Actin Cytoskeleton↗

PubMed2006

[6]-Gingerol induces cell cycle arrest and cell death of mutant p53-expressing pancreatic cancer cells.

[6]-Gingerol, a major phenolic compound derived from ginger, has anti-bacterial, anti-inflammatory and anti-tumor activities. While several molecular mechanisms have been described to underlie its effects on cells in vitro and in vivo, the underlying mechanisms by which [6]-gingerol exerts anti-tumorigenic effects are largely unknown. The purpose of this study was to investigate the action of [6]-gingerol on two human pancreatic cancer cell lines, HPAC expressing wild- type (wt) p53 and BxPC-3 expressing mutated p53. We found that [6]-gingerol inhibited the cell growth through cell cycle arrest at G1 phase in both cell lines. Western blot analyses indicated that [6]-gingerol decreased both Cyclin A and Cyclin-dependent kinase (Cdk) expression. These events led to reduction in Rb phosphorylation followed by blocking of S phase entry. p53 expression was decreased by [6]-gingerol treatment in both cell lines suggesting that the induction of Cyclin-dependent kinase inhibitor, p21cip1, was p53-independent. [6]-Gingerol induced mostly apoptotic death in the mutant p53-expressing cells, while no signs of early apoptosis were detected in wild type p53-expressing cells and this was related to the increased phosphorylation of AKT. These results suggest that [6]-gingerol can circumvent the resistance of mutant p53- expressing cells towards chemotherapy by inducing apoptotic cell death while it exerts cytostatic effect on wild type p53- expressing cells by inducing temporal growth arrest.

Antineoplastic Agents↗

PubMed1999

Cyclosporine A-induced cell cycle arrest and cell death in renal epithelial cells.

We studied the effects of cyclosporine A (CsA) on the proliferation of LLC-PK1 proximal tubule epithelial cells. DNA damage was found to be an early event in CsA nephrotoxicity and could be a sensitive indicator of CsA injury in renal epithelial cells. Cell cycle arrest induced by CsA was coincident with elevated p53 levels. It is possible that trans-activating p21 may mediate the halting of the cell cycle through the CsA-induced accumulation of p53.

Animals↗

PubMed2006

Inhibition of cell growth and induction of G1-phase cell cycle arrest in hepatoma cells by steroid extract from Meretrix meretrix.

In this study, we report that the steroid extract 5alpha, 8alpha-epidioxycholest-6-ene-3beta-ol (MME) from Meretrix meretrix has the ability to inhibit growth of hepatoma cells and to induce G1-phase cell cycle arrest in two human hepatoma cell lines, HepG2 and Hep3B. HepG2 cells were more sensitive than Hep3B to MME. The extract markedly up-regulated the expression of p53 and p21WAF1/CIP1 in HepG2, suggesting that MME-induced G1 phase cell cycle arrest in HepG2 might be p53-dependent. Therefore, the up-regulation of p27KIP1and p16INK4A in both cell lines indicates that a p53-independent pathway might be involved in the mechanism of MME inducing cell cycle arrest. In conclusion, MME induces G1 phase cell cycle arrest via both p53-dependent and p53-independent pathways.

Bivalvia↗

PubMed2000

Differences in the induction of DNA damage, cell cycle arrest, and cell death by 5-fluorouracil and antifolates.

Thymidylate synthase (TS) is an important target for chemotherapy and can be inhibited by 5-fluorouracil (5-FU) and the antifolates, AG337 (Nolatrexed) and multitargeted antifolate (MTA or Pemetrexed). In addition, 5-FU can be incorporated into RNA and DNA, and MTA can inhibit two other enzymes. It is, however, unclear to what extent these differences in drug action will influence activation of downstream mechanisms mediated via TS inhibition. Therefore, two human colon cancer cell lines, WiDr and Lovo, with a different clonogenic origin, were treated with equitoxic concentrations of 5-FU, AG337, and MTA to determine the induction of DNA damage, cell cycle arrest, downstream protein expression, and cell death. At these concentrations, the specific TS inhibitor AG337 induced more DNA damage (up to 20%) than MTA and 5-FU. FACS analysis showed that all drugs induced S phase arrest in Lovo and WiDr that was most pronounced after 5-FU and AG337 exposure (50-70%). Western blotting showed that p53 induction was not detectable in mutant (mt) p53 WiDr and increased much earlier in wild-type (wt) Lovo cells after 5-FU and MTA (24 h) than after AG337 exposure (72 h). In contrast to 5-FU-treated Lovo cells, the bcl-2/bax ratio decreased after antifolate exposure. Nevertheless, both 5-FU and antifolates induced similar amounts of cell death (up to 60%). These results demonstrate that in human colon cancer cells differences in downstream events between AG337 and 5-FU or MTA are related to the additional effects of 5-FU and MTA, which are not associated with TS inhibition.

Antimetabolites, Antineoplastic↗

PubMed2006

Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxy-geldanamycin in Hodgkin's lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest and cell death.

PURPOSE: Heat shock protein 90 (HSP90) is a chaperone for several client proteins involved in transcriptional regulation, signal transduction, and cell cycle control. HSP90 is abundantly expressed by a variety of tumor types and has been recently targeted for cancer therapy. The objective of this study was to determine the role of HSP90 in promoting growth and survival of Hodgkin's lymphoma and to determine the molecular consequences of inhibiting HSP90 function by the small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG) in Hodgkin's lymphoma. EXPERIMENTAL DESIGN: HSP90 expression in Hodgkin's lymphoma cell lines was determined by Western blot and in primary lymph node sections from patients with Hodgkin's lymphoma by immunohistochemistry. Cell viability was determined by the 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Apoptosis and cell cycle fractions were determined by flow cytometry. Expression of intracellular proteins was determined by Western blot. RESULTS: HSP90 is overexpressed in primary and cultured Hodgkin's lymphoma cells. Inhibition of HSP90 function by 17-AAG showed a time- and dose-dependent growth inhibition of Hodgkin's lymphoma cell lines. 17-AAG induced cell cycle arrest and apoptosis, which were associated with a decrease in cyclin-dependent kinase (CDK) 4, CDK 6, and polo-like kinase 1 (PLK1), and induced apoptosis by caspase-dependent and caspase-independent mechanisms. Furthermore, 17-AAG depleted cellular contents of Akt, decreased extracellular signal-regulated kinase (ERK) phosphorylation, and reduced cellular FLICE-like inhibitory protein levels (FLIP), and thus enhanced the cytotoxic effect of doxorubicin and agonistic anti-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor antibodies. CONCLUSION: Inhibition of HSP90 function induces cell death and enhances the activity of chemotherapy and anti-tumor necrosis factor-related apoptosis-inducing ligand death receptor antibodies, suggesting that targeting HSP90 function might be of therapeutic value in Hodgkin's lymphoma.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Antisense oligonucleotide of WAF1 gene prevents EGF-induced cell-cycle arrest in A431 cells.

A431 cells hyperproduce EGF receptors and possess inactive p53 proteins. It has been suggested that a cyclin-dependent kinase (CDK) inhibitor p21/WAF1 plays a crucial role in the EGF-induced cell-cycle arrest of A431 cells. Here, we investigated the role of WAF1 gene transcription in the EGF-induced cell-cycle arrest by transfecting the 18-mer antisense oligonucleotide which corresponds to the 5' region of WAF1 gene (AS/WAF1). When A431 cells were treated with EGF, a cascade of responses were observed, including immediate hyperphosphorylation of EGF receptor on tyrosine residues, accumulation of WAF1 mRNA and p21/WAF1 protein, dephosphorylation of RB protein which is a substrate of CDK-cyclin, and cell-cycle arrest. In the presence of AS/WAF1, EGF induced the tyrosine-phosphorylation of EGF receptor, but WAF1 mRNA was reduced to a half; accumulation of p21/WAF1 protein and its downstream responses were no longer observed; A431 cells grew continuously. Thus, the transfection of antisense efficiently prevented A431 cells from the EGF-induced arrest. These observations suggest that p21/WAF1 protein is a major effector molecule of the EGF-mediated cell-cycle arrest of A431 cells.

Cell Cycle↗

PubMed2003

Perillyl alcohol and perillaldehyde induced cell cycle arrest and cell death in BroTo and A549 cells cultured in vitro.

The role of the monoterpenes, especially limonene and perillyl alcohol, in the treatment of certain cancers is currently being evaluated in clinical trials. In this study, the effects of perillyl alcohol (POH) and its analog, perillaldehyde (PALD), on human carcinoma cell lines (BroTo and A549) cultured in vitro were investigated using proliferation assays (MTT and colony formation) and DNA content analysis by flow cytometry. POH and PALD elicited dose- and time-dependent inhibition of proliferation in both cell lines. Concentrations of POH and PALD that inhibited cell proliferation by 50% (IC50) in 24 hr were 1 and 3 mM, respectively. DNA content analysis revealed that 1 mM of either POH or PALD caused cell cycle arrest in the G1 phase in both cell lines while POH alone caused increased hypodiploid and annexin V-positive populations in both BroTo and A549 cells. POH induced apoptosis and was more effective than PALD at inhibiting the proliferation of BroTo and A549 cells cultured in vitro.

Adenocarcinoma↗

PubMed2000

Human immunodeficiency virus type 1 Vpr-mediated G(2) cell cycle arrest: Vpr interferes with cell cycle signaling cascades by interacting with the B subunit of serine/threonine protein phosphatase 2A.

The Vpr protein of primate lentiviruses arrests cell cycling at the G(2)/M phase through an inactivation of cyclin B-p34(cdc2) and its upstream regulator cdc25. We provide here biochemical and functional evidence demonstrating that human immunodeficiency virus type 1 (HIV-1) Vpr mediates G(2) arrest by forming a complex with protein phosphatase 2A (PP2A), an upstream regulator of cdc25. Vpr associates with PP2A through a specific interaction with the B55 regulatory subunit. This interaction is necessary but not sufficient for G(2) arrest. Interestingly, we found that Vpr association with B55-containing PP2A targets the enzymatic complex to the nucleus and, importantly, enhances the recruitment and dephosphorylation of the cdc25 substrate. Our data suggest that Vpr mediates G(2) arrest by enhancing the nuclear import of PP2A and by positively modulating its catalytic activity towards active phosphorylated nuclear cdc25.

Amino Acid Sequence↗

PubMed2005

TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity.

TP53INP1 is an alternatively spliced gene encoding two nuclear protein isoforms (TP53INP1alpha and TP53INP1beta), whose transcription is activated by p53. When overexpressed, both isoforms induce cell cycle arrest in G1 and enhance p53-mediated apoptosis. TP53INP1s also interact with the p53 gene and regulate p53 transcriptional activity. We report here that TP53INP1 expression is induced during experimental acute pancreatitis in p53-/- mice and in cisplatin-treated p53-/- mouse embryo fibroblasts (MEFs). We demonstrate that ectopic expression of p73, a p53 homologue, leads to TP53INP1 induction in p53-deficient cells. In turn, TP53INP1s alters the transactivation capacity of p73 on several p53-target genes, including TP53INP1 itself, demonstrating a functional association between p73 and TP53INP1s. Also, when overexpressed in p53-deficient cells, TP53INP1s inhibit cell growth and promote cell death as assessed by cell cycle analysis and colony formation assays. Finally, we show that TP53INP1s potentiate the capacity of p73 to inhibit cell growth, that effect being prevented when the p53 mutant R175H is expressed or when p73 expression is blocked by a siRNA. These results suggest that TP53INP1s are functionally associated with p73 to regulate cell cycle progression and apoptosis, independently from p53.

Acute Disease↗

PubMed2003

Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death.

We have previously shown a critical role for IFN regulatory factor 5 (IRF-5) in the innate immune response to virus infection. For the first time, we now show that although IRF-5 is a direct target of p53, its cell cycle regulatory and proapoptotic effects are p53 independent. IRF-5 inhibits both in vitro and in vivo B-cell lymphoma tumor growth in the absence of wild-type p53. The molecular mechanism(s) of IRF-5-mediated growth inhibition is associated with a G(2)-M cell cycle arrest and modulation of growth regulatory and proapoptotic genes, including p21, Bak, DAP kinase 2, and Bax. Taken together, these data indicate that although IRF-5 is a downstream target of p53, its growth inhibitory and proapoptotic effects are independent of p53.

Animals↗