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PubMed2005

The role of alternative oxidase in modulating carbon use efficiency and growth during macronutrient stress in tobacco cells.

When wild-type (wt) tobacco (Nicotiana tabacum cv. Petit Havana SR1) cells are grown under macronutrient (P or N) limitation, they induce large amounts of alternative oxidase (AOX), which constitutes a non-energy-conserving branch of the respiratory electron transport chain. To investigate the significance of AOX induction, wt cells were compared with transgenic (AS8) cells lacking AOX. Under nutrient limitation, growth of wt cell cultures was dramatically reduced and carbon use efficiency (g cell dry weight gain g(-1) sugar consumed) decreased by 42-63%. However, the growth of AS8 was only moderately reduced by the nutrient deficiencies and carbon use efficiency values remained the same as under nutrient-sufficient conditions. As a result, the nutrient limitations more severely compromised the tissue nutrient status (P or N) of AS8 than wt cells. Northern analyses and a comparison of the mitochondrial protein profiles of wt and AS8 cells indicated that the lack of AOX in AS8 under P limitation was associated with increased levels of proteins commonly associated with oxidative stress and/or stress injury. Also, the level of electron transport chain components was consistently reduced in AS8 while tricarboxylic acid cycle enzymes did not show a universal trend in abundance in comparison to the wt. Alternatively, the lack of AOX in AS8 cells under N limitation resulted in enhanced carbohydrate accumulation. It is concluded that AOX respiration provides an important general mechanism by which plant cells can modulate their growth in response to nutrient availability and that AOX also has nutrient-specific roles in maintaining cellular redox and carbon balance.

Carbon↗
PubMed2005

Conserved and specific functions of mammalian ssu72.

We describe the cloning and characterization of a human homolog of the yeast transcription/RNA-processing factor Ssu72, following a yeast two-hybrid screen for pRb-binding factors in the prostate gland. Interaction between hSsu72 and pRb was observed in transfected mammalian cells and involved multiple domains in pRb; however, so far, mutual effects of these two factors could not be demonstrated. Like the yeast counterpart, mammalian Ssu72 associates with TFIIB and the yeast cleavage/polyadenylation factor Pta1, and exhibits intrinsic phosphatase activity. Mammals contain a single ssu72 gene and a few pseudogenes. During mouse embryogenesis, ssu72 was highly expressed in the nervous system and intestine; high expression in the nervous system persisted in adult mice and was also readily observed in multiple human tumor cell lines. Both endogenous and ectopically expressed mammalian Ssu72 proteins resided primarily in the cytoplasm and only partly in the nucleus. Interestingly, fusion to a strong nuclear localization signal conferred nuclear localization only in a fraction of transfected cells, suggesting active tethering in the cytoplasm. Suppression of ssu72 expression in mammalian cells by siRNA did not reduce proliferation/survival, and its over-expression did not affect transcription of candidate genes in transient reporter assays. Despite high conservation, hssu72 was unable to rescue an ssu72 lethal mutation in yeast. Together, our results highlight conserved and mammalian specific characteristics of mammalian ssu72.

Amino Acid Sequence↗
PubMed2005

Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss.

In this study, we report the biochemical characterization of the deafness-associated mitochondrial 12S rRNA C1494T mutation using 27 cybrid cell lines constructed by transferring mitochondria from 9 lymphoblastoid cell lines derived from a Chinese family into human mitochondrial DNA (mtDNA)-less (rho degrees) cells. Six cybrids derived from two asymptomatic members, and nine cybrids derived from three symptomatic members of the Chinese family carrying the C1494T mutation exhibited approximately 38 and 43% decrease in the rate of mitochondrial protein labeling, respectively, compared with twelve cybrids derived from four Chinese control individuals. These defects are apparently a primary contributor to significant reductions in the rate of overall respiratory capacity or the rate of malate/glutamate promoted respiration, or succinate/G3P-promoted respiration, or TMPD/ascorbate-promoted respiration in mutant cybrid cell lines derived from either symptomatic or asymptomatic individuals. Furthermore, the very significant/nearly identical increase in the ratio of doubling times in DMDM medium in the presence/absence of high concentration of paromomycin was observed in symptomatic or asymptomatic cybrid cell lines carrying the C1494T mutation as compared with the average rate in control cell lines. These observations provide the direct biochemical evidences that the C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and non-syndromic hearing loss. In addition, these data provide the first biochemical evidence that nuclear background plays a critical role in the phenotypic manifestation of non-syndromic hearing loss and aminoglycoside toxicity associated with the C1494T mutation.

Cell Growth Processes↗
PubMed2005

Expression of exogenous human telomerase in cultures of endometrial stromal cells does not alter their hormone responsiveness.

In the human endometrium, stromal cells mediate the proliferative response of epithelial cells to the steroid hormones estrogen and progesterone. These stromal-epithelial interactions are readily studied in vitro by coculture of both cell types. A major impediment to such studies is the rapid senescence of normal stromal cells. To circumvent this problem, we tested whether human endometrial stromal cells immortalized by expressing a transduced human telomerase reverse transcriptase (TERT) subunit retained the ability to mediate hormonal control of epithelial proliferation in the coculture assay. We found that the telomerized stromal cells were very similar to the parental strain from which they were derived according to criteria of proliferation, karyotype, cellular localization of cytoskeletal markers and nuclear staining, and basal gene expression based on microarray analysis. We also showed that expression of estrogen and progesterone receptors, as assessed by immunodetection, was similar in both telomerized and parental stromal cells. Importantly, the telomerized stromal cells were shown in coculture assay to be as effective as normal stromal cells in regulating the proliferation of endometrial epithelial cells in response to estrogen or progesterone. The availability of these long-lived stromal cells may advance studies addressing the mechanistic, regulatory, and cell structural basis of stromal-epithelial interactions and hormonal responses in normal, preneoplastic, and neoplastic human endometrial tissue.

Blotting, Western↗
PubMed1988

DNA topoisomerases as targets for chemotherapy.

DNA topoisomerases are ubiquitous enzymes that alter the configuration or topology of DNA. These enzymes play an important role in replicational, recombinational, and transcriptional events and are a key to cell growth processes. A number of therapeutically useful drugs apparently exert their effects by interfering with DNA topoisomerization reactions. Several inhibitors of bacterial DNA topoisomerase II (DNA gyrase) have been developed. Most of these possess a 4-quinolone nucleus and are highly bactericidal for a variety of microorganisms; at therapeutically effective levels, these compounds do not inhibit the human topoisomerases. Other drugs, structurally distinct from the DNA gyrase inhibitors, inhibit the human type II DNA topoisomerase. These drugs, including m-AMSA and VP16-23, are proving useful in the treatment of several neoplasms.

Animals↗
PubMed2005

An in vitro model for dissecting distraction osteogenesis.

Distraction osteogenesis (DO) is a mechanotransduction process capable of generating viable osseous tissue by the gradual separation of osteotomized bone edges. Several variables are implicated in DO: magnitude of mechanical strain, distraction rate, and type of distracted bone. The combination of these factors acts on different types of cells inducing apoptosis, cell proliferation, and differentiation. The elucidation of the molecular mechanisms has important clinical implications because it may facilitate the use of recombinant proteins or gene therapy to accelerate bone regeneration. Previous reports have analyzed several molecules such as extracellular matrix proteins, cytokines, bone morphogenetic proteins, hormones, and angiogenic factors. Moreover, a single protein can have multifunctional roles. With such a huge number of mechanical, histologic, cellular, and molecular variables, there is the need to have a cell culture model that enables the selection of the effect of a specific strength to a single cell type at different time points and with or without cytokines. The analysis of the genetic profiling of a cell line cultured on an equibiaxial stretch device has such characteristic. Because there is a recruitment and commitment of preosteoblastic cells during bone lengthening and no previous report has focus on them, the authors used a preosteoblast MC3T3-E1 cell line to detect the early molecular effects of distraction on mesenchymal cells. By using DNA microarrays containing 15,000 clones, the authors identified several genes the expression of which was significantly up- or down-regulated. The differentially expressed genes cover a broad range of biological processes: cell growth, metabolism, morphogenesis, cell communication, response to stress, and cell death. The data reported are the first genetic portrait of stretched preosteoblasts. They can be relevant in the better understanding of the molecular mechanism of DO and as a model for comparing the effect of distraction on different cell lines and primary cultures, rate and strength of distraction, and with or without cytokines.

3T3 Cells↗
PubMed2006

Effect of methylation-associated silencing of the death-associated protein kinase gene on nasopharyngeal carcinoma.

Death-associated protein kinase (DAPK) is a Ca/calmodulin-regulated serine/threonine kinase and a positive mediator of apoptosis. Loss of expression of the DAPK gene by aberrant promoter methylation may play an important role in cancer development and progression. The aim of this study was to investigate the frequency of gene promoter methylation of DAPK in nasopharyngeal carcinoma (NPC) and the effect of 5-Aza-2'-deoxycytidine (5-Aza-CdR), a demethylating agent, on CNE cells, a human nasopharyngeal carcinoma cell line, and on xenografts of CNE cells. Methylation-specific PCR and RT-PCR were used to determine the promoter methylation status and mRNA expression of the DAPK gene in NPC. Furthermore, CNE cells were treated in vitro and in vivo with 5-Aza-CdR to explore the effect of demethylating agents on DAPK mRNA expression and tumor growth. Hypermethylation of the DAPK gene promoter was found in 35 (76.1%) of 46 NPC samples. There was no significant difference in the promoter hypermethylation rate among samples from patients with different TNM stages. No promoter hypermethylation of the DAPK gene was found in all six chronic inflammatory nasopharyngeal tissue specimens. DAPK mRNA expression was not detected in NPC tumor specimens with promoter hypermethylation. However, DAPK mRNA expression was observed in unmethylated NPC tumors and in the chronic inflammatory nasopharyngeal tissue specimens. Promoter hypermethylation of the DAPK gene was found and no DAPK mRNA expression was detected in CNE cells. DAPK mRNA expression in CNE cells and xenografts could be restored by treatment with 5-Aza-CdR. The CNE cell xenografts of nude mice treated with 5-Aza-CdR were obviously smaller in tumor volume than those of nude mice treated with PBS. These results demonstrate that loss of DAPK expression could be associated with promoter region methylation in NPC. 5-Aza-CdR may slow the growth of CNE cells in vitro and in vivo by reactivating the DAPK gene silenced by de novo methylation.

Adult↗
PubMed2006

Anti-tumor activity of Titanocene Y in xenografted Caki-1 tumors in mice.

The benzyl-substituted unbridged titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against human renal cancer cells (Caki-1), in which it showed an IC50 value of 36 x 10 mol/l. Titanocene Y was then given in vivo in doses of 10, 20, 30, 40 and 50 mg/kg on 5 consecutive days to Caki-1-bearing mice, and it showed concentration-dependent and statistically significant tumor growth reduction with respect to a solvent-treated control cohort. The maximum tolerable dose of Titanocene Y was determined to be 40 mg/kg and it showed significantly better tumor volume growth reduction than cisplatin given at a dose of 2 mg/kg. This superior activity of Titanocene Y with respect to cisplatin will hopefully lead to clinical tests against metastatic renal cell cancer in the near future.

Animals↗
PubMed2005

Interferon-gamma, but not interferon-alpha, induces SOCS 3 expression in human melanoma cell lines.

The signal transducers and transcription activators (STATs) and their endogenous inhibitors of the suppressors of cytokine signalling (SOCS) family are major proteins harmonizing the transmission of external signals from the surface membrane to target genes in the nucleus. To correlate the induction of SOCS 3 by interferons (IFNs) on messenger RNA and protein levels with STAT 1 phosphorylation in human malignant melanoma cell lines, we used a unique collection of 18 established malignant melanoma cell lines and six human non-malignant normal cells (two melanocytes, two skin keratinocytes and two fibroblasts). IFN-gamma induced SOCS 3 in 83% of melanoma cell lines, whereas IFN-alpha stimulated SOCS 3 expression in only 11% of cases. Similarly, melanocytes showed strong induction of SOCS 3 by IFN-gamma and, to a lesser extent, by IFN-alpha. In most cases, SOCS 3 expression was paralleled by STAT 1 phosphorylation at tyrosine residues (Y701). In several lines, however, SOCS 3 was not induced despite STAT 1 phosphorylation and, in a few lines, SOCS 3 induction occurred without detectable STAT 1 phosphorylation, indicating that STAT 1 might not be an exclusive inducer of SOCS 3. Similarly, non-malignant cells displayed STAT 1 activation and high levels of SOCS 3 expression after IFN-gamma (but not IFN-alpha) treatment. In conclusion, in contrast to IFN-alpha, IFN-gamma appeared to induce SOCS 3 apparently at the transcription level and exhibited higher cytotoxic effects regardless of the cell origin.

Blotting, Northern↗
PubMed2006

Pannarin inhibits cell growth and induces cell death in human prostate carcinoma DU-145 cells.

In the course of our continuing search for new natural anticancer compounds for treatment and/or prevention of prostate cancer, our laboratory has focused its search on poorly investigated lichen metabolites, sphaerophorin, pannarin and epiphorellic acid-1. To this end, we treated DU-145, a cell line resembling the last stage of prostate carcinoma, with different concentrations (6-50 micromol/l) of these compounds for 72 h. Our data clearly evidenced that these lichen metabolites inhibit the growth of human prostate carcinoma DU-145 cells, but pannarin exhibits a higher effect. Our data show an induction of apoptotic death of advanced prostate cancer cells by sphaerophorin, pannarin and epiphorellic acid-1. In fact, a significant (P<0.001) increase in caspase-3 enzyme activity occurred in DU-145 cells treated with all lichen compounds at 12 and 25 micromol/l concentrations, correlated to a high DNA fragmentation, but without the disruption of the plasma membrane, as evaluated by the percentage of lactic dehydrogenase release. Alternatively, we found a low, but significant (P<0.01) lactic dehydrogenase release at higher concentrations (50 micromol/l), suggesting that in these experimental conditions sphaerophorin, pannarin and epiphorellic acid-1 induce necrosis in DU-145 cells, through the increase in reactive oxygen species generation. The experimental evidence is further confirmed by caspase-3 activity results, evidencing a reduction in the activity of this protease at a higher concentration, 50 micromol/l.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Spatiotemporal fluctuation-induced transition in a tumor model with immune surveillance.

We report on a simple model of spatially extended antitumor system with a fluctuation in growth rate, which can undergo a nonequilibrium phase transition. Three states as excited, subexcited and nonexcited states of a tumor are defined to describe its growth. The multiplicative noise is found to have opposite effects: The positive effect on a nonexcited tumor and the negative effect on an excited tumor.

Animals↗
PubMed2005

Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo.

Current treatment modalities for malignant gliomas do not allow long-term survival. Here, we identify suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylases (HDAC), as an effective experimental anti-glioma agent. Administration of SAHA to various glioma cell lines obtained from human, rat and mouse inhibited tumour cell growth in a range of 1-10 microm. This anti-glioma property is associated with up-regulation of the cell cycle control protein p21/WAF, as well as the induction of apoptosis. A novel tumour invasion model using slice cultures of rat brain corroborated the anti-glioma properties of SAHA in the organotypic brain environment. In this model, glioma invasion compromised adjacent brain parenchyma, and this tumour-associated cytotoxicity could be inhibited by SAHA. In addition, a 10-fold dose escalation experiment did not challenge the viability of cultured brain slices. In vivo, a single intratumoural injection of SAHA 7 days after orthotopic implantation of glioma cells in syngeneic rats doubled their survival time. These observations identify chromatin-modifying enzymes as possible and promising targets for the pharmacotherapy of malignant gliomas.

Acetylation↗
PubMed2006

Growth inhibitory effects of pegylated IFN alpha-2b on human liver cancer cells in vitro and in vivo.

PURPOSE: We investigated the effects of pegylated IFN-alpha2b (PEG-IFN-alpha2b) on the growth of human liver cancer cells. METHODS: The effect of PEG-IFN-alpha2b on the proliferation of 13 liver cancer cell lines was investigated in vitro. Chronological changes in growth and IFN-alpha receptor-2 (IFNAR-2) expression were monitored in hepatocellular carcinoma (HCC) cells (HAK-1B) cultured with PEG-IFN-alpha2b. After HAK-1B cells were transplanted into nude mice, various doses of PEG-IFN-alpha2b or IFN-alpha2b were administered, and tumor volume, weight, histology, and IFNAR-2 expression were examined. RESULTS: PEG-IFN-alpha2b inhibited the growth of nine cell lines with apoptosis in a dose- and time-dependent manner. Continuous contact with PEG-IFN-alpha2b induced time-dependent growth inhibition and down-regulation of IFNAR-2 expression. PEG-IFN-alpha2b induced a dose-dependent decrease in tumor volume and weight, a significant increase of apoptotic cells, and a decrease in IFNAR-2 expression in the tumor. The clinical dose for chronic hepatitis C was also effective. The antitumor effect of PEG-IFN-alpha2b was significantly stronger than that of non-PEG-IFN-alpha2b in vivo. CONCLUSIONS: Continuous contact with PEG-IFN-alpha2b induces strong antitumor effects and the down-regulation of IFNAR-2 in HCC cells. The data suggest potential clinical application of PEG-IFN-alpha2b for the prevention and treatment of HCC.

Animals↗
PubMed2005

A novel group of genes regulates susceptibility to antineoplastic drugs in highly tumorigenic breast cancer cells.

Doxorubicin is an anthracycline antibiotic used for cancer chemotherapy. The utility of doxorubicin is limited by its inability to kill all of the cells within a tumor and by resistant cells emerging from the treated population. We have screened for genes that regulate doxorubicin susceptibility in highly tumorigenic breast cancer cells by cDNA microarray and RNA interference (RNAi) analysis, and we have identified genes associated with both proliferation and cell cycle arrest after doxorubicin treatment. We confirmed that MDA-MB-231 cells treated with doxorubicin induce the expression of carbonic anhydrase II (CAII), inhibitor of differentiation/DNA binding 2 (Id2), activating transcription factor 3 (Atf3), and the phosphatidylinositol 3-kinase 55-kDa regulatory subunit p55PIK. These genes were induced at different times and with varying specificities to different chemotherapeutic drugs. In addition to being induced at the transcriptional level, the CAII and clusterin proteins were elevated after doxorubicin treatment. CAII, Id2, p55PIK, and clusterin were not altered by doxorubicin in MCF-7 cells, a weakly tumorigenic cell line used in previous studies of doxorubicin-regulated gene expression. By inhibiting gene expression using RNAi, we found that CAII and clusterin increase cell survival after doxorubicin treatment, whereas Id2 increases susceptibility to doxorubicin. Our results support a model in which highly tumorigenic breast cancer cells induce a transcriptional response to doxorubicin that is distinct from less malignant cells. The induced genes regulate drug susceptibility positively and negatively and may be novel targets for therapeutic intervention.

Antineoplastic Agents↗
PubMed2004

The strength of indecisiveness: oscillatory behavior for better cell fate determination.

Oscillatory behavior is very common in many cellular responses. Recently, two pathways involved in response to cell stress, the p53 and nuclear factor kappa B signaling pathways, have been found to show oscillatory behavior. At first sight, there would seem to be no reason for signaling pathways of this type to require oscillations. Recent single-cell studies indicate that oscillatory behavior may be used to allow repeated testing for the continued existence of a signal. I argue that oscillations increase cellular response sensitivity and flexibility by allowing the cell to integrate the results of many periodical evaluations of the signal before making an eventual decision about cell fate, thus reducing the risk of premature commitment.

Animals↗
PubMed2003

Production of high-quality particulate methane monooxygenase in high yields from Methylococcus capsulatus (bath) with a hollow-fiber membrane bioreactor.

In order to obtain particulate methane monooxygenase (pMMO)-enriched membranes from Methylococcus capsulatus (Bath) with high activity and in high yields, we devised a method to process cell growth in a fermentor adapted with a hollow-fiber bioreactor that allows easy control and quantitative adjustment of the copper ion concentration in NMS medium over the time course of cell culture. This technical improvement in the method for culturing bacterial cells allowed us to study the effects of copper ion concentration in the growth medium on the copper content in the membranes, as well as the specific activity of the enzyme. The optimal copper concentration in the growth medium was found to be 30 to 35 micro M. Under these conditions, the pMMO is highly expressed, accounting for 80% of the total cytoplasmic membrane proteins and having a specific activity as high as 88.9 nmol of propylene oxide/min/mg of protein with NADH as the reductant. The copper stoichiometry is approximately 13 atoms per pMMO molecule. Analysis of other metal contents provided no evidence of zinc, and only traces of iron were present in the pMMO-enriched membranes. Further purification by membrane solubilization in dodecyl beta-D-maltoside followed by fractionation of the protein-detergent complexes according to molecular size by gel filtration chromatography resulted in a good yield of the pMMO-detergent complex and a high level of homogeneity. The pMMO-detergent complex isolated in this way had a molecular mass of 220 kDa and consisted of an alphabetagamma protein monomer encapsulated in a micelle consisting of ca. 240 detergent molecules. The enzyme is a copper protein containing 13.6 mol of copper/mol of pMMO and essentially no iron (ratio of copper to iron, 80:1). Both the detergent-solubilized membranes and the purified pMMO-detergent complex exhibited reasonable, if not excellent, specific activity. Finally, our ability to control the level of expression of the pMMO allowed us to clarify the sensitivity of the enzyme to NADH and duroquinol, the two common reductants used to assay the enzyme.

Amino Acid Sequence↗
PubMed2006

Specific amino acid residues in the basic helix-loop-helix domain of SRC-3 are essential for its nuclear localization and proteasome-dependent turnover.

SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM-1 is a primary transcriptional coactivator for the estrogen receptor. Here we report that deletion of the SRC-3 basic helix-loop-helix (bHLH) domain blocks its proteasome-dependent turnover. We further identified two residues (K17 and R18) in the SRC-3 bHLH domain that are essential for its stability. Moreover, we found that the bHLH domain contains a bipartite nuclear localization signal (NLS). SRC-3 NLS mutants block its translocation into the nucleus, and this correlates with its insensitivity to proteasome-dependent turnover. SRC-3 shows a time-dependent decay in the presence of cycloheximide which is not apparent for the cytoplasmic mutant. Fusion of a simian virus 40 T antigen NLS to the cytoplasmic localized SRC-3 mutant drives it back into the nucleus and restores its proteasomal sensitivity. In addition, the cytoplasmic mutants are inactive for transcriptional coactivation and cancer cell growth. Taken together, our data indicate that proteasome-dependent turnover of SRC-3 occurs in the nucleus and that two amino acid residues in the bHLH domain provide a signal for its nuclear localization and proteasome-dependent degradation as well as for regulation of SRC-3 transcriptional coactivator capacity.

Active Transport, Cell Nucleus↗
PubMed2006

Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals.

Homeodomain-interacting protein kinase 1 (Hipk1), 2, and 3 genes encode evolutionarily conserved nuclear serine/threonine kinases, which were originally identified as interacting with homeodomain-containing proteins. Hipks have been repeatedly identified as interactors for a vast range of functional proteins, including not only transcriptional regulators and chromatin modifiers but also cytoplasmic signal transducers, transmembrane proteins, and the E2 component of SUMO ligase. Gain-of-function experiments using cultured cells indicate growth regulatory roles for Hipks on receipt of morphogenetic and genotoxic signals. However, Hipk1 and Hipk2 singly deficient mice were grossly normal, and this is expected to be due to a functional redundancy between Hipk1 and Hipk2. Therefore, we addressed the physiological roles of Hipk family proteins by using Hipk1 Hipk2 double mutants. Hipk1 Hipk2 double homozygotes are progressively lost between 9.5 and 12.5 days postcoitus and frequently fail to close the anterior neuropore and exhibit exencephaly. This is most likely due to defective proliferation in the neural fold and underlying paraxial mesoderm, particularly in the ventral region, which may be attributed to decreased responsiveness to Sonic hedgehog signals. The present study indicated the overlapping roles for Hipk1 and Hipk2 in mediating cell proliferation and apoptosis in response to morphogenetic and genotoxic signals during mouse development.

Animals↗