Showing papers on "Cell growth published in 1999"
TL;DR: The c-myc gene was discovered as the cellular homolog of the retroviral v- myc oncogene 20 years ago and found to be activated in various animal and human tumors, suggesting that it is critical for development.
Abstract: The c-myc gene was discovered as the cellular homolog of the retroviral v-myc oncogene 20 years ago (23, 25, 167). The c-myc proto-oncogene was subsequently found to be activated in various animal and human tumors (37, 39, 42). It belongs to the family of myc genes that includes B-myc, L-myc, N-myc, and s-myc; however, only c-myc, L-myc, and N-myc have neoplastic potential (54, 82, 102, 118, 178). Targeted homozygous deletion of the murine c-myc gene results in embryonic lethality, suggesting that it is critical for development (43). Homozygous inactivation of c-myc in rat fibroblasts caused a marked prolongation of cell doubling time, further suggesting a central role for c-myc in regulating cell proliferation (121).
The frequency of genetic alterations of c-myc in human cancers (42) has allowed an estimation that approximately 70,000 U.S. cancer deaths per year are associated with changes in the c-myc gene or its expression. Given that c-myc may contribute to one-seventh of U.S. cancer deaths, recent efforts have been directed toward understanding the function of the c-Myc protein in cancer biology with the hope that therapeutic insights will emerge. Past efforts, which have contributed significantly to our current understanding of c-myc, are discussed in a number of excellent reviews (23, 29, 37, 40, 44, 52, 66, 82, 94, 102, 118, 125, 132, 145, 178, 182, 186).
1,630 citations
TL;DR: The cloning of mox1 is described, which encodes a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase of phagocytes, gp91phox, which is expressed in colon, prostate, uterus and vascular smooth muscle, but not in peripheral blood leukocytes.
Abstract: Reactive oxygen species (ROS) generated in some non-phagocytic cells are implicated in mitogenic signalling and cancer. Many cancer cells show increased production of ROS, and normal cells exposed to hydrogen peroxide or superoxide show increased proliferation and express growth-related genes. ROS are generated in response to growth factors, and may affect cell growth, for example in vascular smooth-muscle cells. Increased ROS in Ras-transformed fibroblasts correlates with increased mitogenic rate. Here we describe the cloning of mox1, which encodes a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase of phagocytes, gp91phox. mox1 messenger RNA is expressed in colon, prostate, uterus and vascular smooth muscle, but not in peripheral blood leukocytes. In smooth-muscle cells, platelet-derived growth factor induces mox1 mRNA production, while antisense mox1 mRNA decreases superoxide generation and serum-stimulated growth. Overexpression of mox1 in NIH3T3 cells increases superoxide generation and cell growth. Cells expressing mox1 have a transformed appearance, show anchorage-independent growth and produce tumours in athymic mice. These data link ROS production by Mox1 to growth control in non-phagocytic cells.
1,464 citations
TL;DR: It is shown that NF-κB also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1, and is identified as an important transcriptional target of NF-α, revealing a mechanism to explain how NF-β is involved in the early phases of the cell cycle to regulate cell growth and differentiation.
Abstract: Accumulating evidence implicates the transcription factor NF-kappaB as a positive mediator of cell growth, but the molecular mechanism(s) involved in this process remains largely unknown. Here we use both a skeletal muscle differentiation model and normal diploid fibroblasts to gain insight into how NF-kappaB regulates cell growth and differentiation. Results obtained with the C2C12 myoblast cell line demonstrate that NF-kappaB functions as an inhibitor of myogenic differentiation. Myoblasts generated to lack NF-kappaB activity displayed defects in cellular proliferation and cell cycle exit upon differentiation. An analysis of cell cycle markers revealed that NF-kappaB activates cyclin D1 expression, and the results showed that this regulatory pathway is one mechanism by which NF-kappaB inhibits myogenesis. NF-kappaB regulation of cyclin D1 occurs at the transcriptional level and is mediated by direct binding of NF-kappaB to multiple sites in the cyclin D1 promoter. Using diploid fibroblasts, we demonstrate that NF-kappaB is required to induce cyclin D1 expression and pRb hyperphosphorylation and promote G(1)-to-S progression. Consistent with results obtained with the C2C12 differentiation model, we show that NF-kappaB also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1. These data therefore identify cyclin D1 as an important transcriptional target of NF-kappaB and reveal a mechanism to explain how NF-kappaB is involved in the early phases of the cell cycle to regulate cell growth and differentiation.
1,353 citations
TL;DR: Although the precise mechanisms by which nonparenchymal cells modulate the hepatocyte phenotype remain unelucidated, some new insights on the modes of cell signaling, the extent of cell–cell interaction, and the ratio of cell populations are noted.
Abstract: Heterotypic cell interaction between parenchymal cells and nonparenchymal neighbors has been reported to modulate cell growth, migration, and/or differentiation. In both the developing and adult liver, cell-cell interactions are imperative for coordinated organ function. In vitro, cocultivation of hepatocytes and nonparenchymal cells has been used to preserve and modulate the hepatocyte phenotype. We summarize previous studies in this area as well as recent advances in microfabrication that have allowed for more precise control over cell-cell interactions through 'cellular patterning' or 'micropatterning'. Although the precise mechanisms by which nonparenchymal cells modulate the hepatocyte phenotype remain unelucidated, some new insights on the modes of cell signaling, the extent of cell-cell interaction, and the ratio of cell populations are noted. Proposed clinical applications of hepatocyte cocultures, typically extracorporeal bioartificial liver support systems, are reviewed in the context of these new findings. Continued advances in microfabrication and cell culture will allow further study of the role of cell communication in physiological and pathophysiological processes as well as in the development of functional tissue constructs for medical applications.
903 citations
TL;DR: It is shown that Id2 is indispensable for normal development of mice and has an essential role in the generation of peripheral lymphoid organs and NK cells.
Abstract: Transcription factors with a basic helix-loop-helix (HLH) motif have been shown to be crucial for various cell differentiation processes during development of multicellular organisms. Id proteins inhibit the functions of these transcription factors in a dominant-negative manner by suppressing their heterodimerization partners through the HLH domains. Members of the Id family also promote cell proliferation, implying a role in the control of cell differentiation. Here we show that Id2 is indispensable for normal development of mice. Id2-/- mice lack lymph nodes and Peyer's patches. However, their splenic architecture is normal, exhibiting T-cell and B-cell compartments and distinct germinal centres. The cell population that produces lymphotoxins, essential factors for the development of secondary lymphoid organs, is barely detectable in the Id2-/- intestine. Furthermore, the null mutants show a greatly reduced population of natural killer (NK) cells, which is due to an intrinsic defect in NK-cell precursors. Our results indicate that Id2 has an essential role in the generation of peripheral lymphoid organs and NK cells.
869 citations
TL;DR: This work has shown that both transcriptional and post‐transcriptional mechanisms modulate the activity of this critical cellular enzyme, glutathione, in a tightly regulated manner in mammalian cells.
Abstract: Glutathione (GSH) is an important intracellular peptide with multiple functions ranging from antioxidant defense to modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the avail- ability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, g-glu- tamylcysteine synthetase (GCS). In the liver, major factors that determine the availability of cysteine are diet, membrane transport activities of the three sulfur amino acids cysteine, cystine and methionine, and the conversion of methionine to cysteine via the trans-sulfuration pathway. Many conditions alter GSH level via changes in GCS activity and GCS gene expression. These include oxidative stress, activators of Phase II detoxifying enzymes, antioxidants, drug- resistant tumor cell lines, hormones, cell prolifera- tion, and diabetes mellitus. Since the molecular cloning of GCS, much has been learned about the regulation of this enzyme. Both transcriptional and post-transcriptional mechanisms modulate the activ- ity of this critical cellular enzyme.—Lu, S. C. Regu- lation of hepatic glutathione synthesis: current con- cepts and controversies. FASEB J. 13, 1169 -1183 (1999)
862 citations
TL;DR: Loss-of-function mutations in the signaling molecules involved in apoptosis cause hyper-proliferation of cells in mouse and human and exaggeration of this death cascade causes the destruction of various tissues.
Abstract: The immune response is regulated not only by cell proliferation and differentiation, but also by programmed cell death, or apoptosis. In response to various stimuli, death factors bind to their respective receptors and activate the apoptotic death program in target cells. A cascade of specific proteases termed caspases mediates the apoptotic process. The activated caspases cleave various cellular components, a process that leads to morphological changes of the cells and nuclei, as well as to degradation of the chromosomal DNA. Loss-of-function mutations in the signaling molecules involved in apoptosis cause hyper-proliferation of cells in mouse and human. In contrast, exaggeration of this death cascade causes the destruction of various tissues.
802 citations
TL;DR: Drosophila deficient in the S6 kinase gene (dS6K) exhibited an extreme delay in development and a severe reduction in body size, and these flies had smaller cells rather than fewer cells.
Abstract: Cell proliferation requires cell growth; that is, cells only divide after they reach a critical size. However, the mechanisms by which cells grow and maintain their appropriate size have remained elusive. Drosophila deficient in the S6 kinase gene ( dS6K ) exhibited an extreme delay in development and a severe reduction in body size. These flies had smaller cells rather than fewer cells. The effect was cell-autonomous, displayed throughout larval development, and distinct from that of ribosomal protein mutants ( Minutes ). Thus, the dS6K gene product regulates cell size in a cell-autonomous manner without impinging on cell number.
750 citations
TL;DR: Development of modulatory strategies targeting this transcription factor may provide a novel therapeutic tool for the treatment or prevention of various diseases.
Abstract: Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that governs the expression of genes encoding cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states. NF-κB is activated by several agents, including cytokines, oxidant free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NF-κB has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete and persistent inhibition of NF-κB has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth. Therefore, development of modulatory strategies targeting this transcription factor may provide a novel therapeutic tool for the treatment or prevention of various diseases.
741 citations
TL;DR: It is indicated that cell cycling related to leaf morphogenesis, tissue-specific patterns of cell proliferation, and cell differentiation occurs concurrently during leaf development and suggest that unique regulatory pathways may operate at each level.
740 citations
TL;DR: How cells ensure that chromosome duplication, chromosome segregation, and cell division occur in the correct order and form an immortal reproductive cycle is one of the most fundamental questions in cell biology.
Abstract: Cell proliferation depends on the duplication of chromosomes followed by the segregation of duplicates (sister chromatids) to opposite poles of the cell prior to cell division (cytokinesis). How cells ensure that chromosome duplication, chromosome segregation, and cell division occur in the correct order and form an immortal reproductive cycle is one of the most fundamental questions in cell biology. Without such coordination, cells would not maintain a constant chromosome number and sexual reproduction as we know and love it would not be possible.
TL;DR: LANA interacts with the tumour suppressor protein p53 and represses its transcriptional activity, which contributes to viral persistence and oncogenesis in KS through its ability to promote cell survival by altering p53 function.
Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, has been implicated in the development of Kaposi's sarcoma (KS) and several B-cell lymphoproliferative diseases1,2,3. Most cells in lesions derived from these malignancies are latently infected, and different viral gene products have been identified in association with lytic or latent infection by KSHV4,5. The latency-associated nuclear antigen (LANA), encoded by open reading frame 73 of the KSHV genome, is a highly immunogenic protein that is expressed predominantly during viral latency, in most KS spindle cells and in cell lines established from body-cavity-based lymphomas6,7. Antibodies to LANA can be detected in a high percentage of HIV-infected individuals who subsequently develop KS8,9, although its role in disease pathogenesis is not completely understood. p53 is a potent transcriptional regulator of cell growth whose induction leads either to cell-cycle arrest or apoptosis. Loss of p53 function correlates with cell transformation and oncogenesis10,11, and several viral oncoproteins interact with p53 and modulate its biological activity12,13. Here we show that LANA interacts with the tumour suppressor protein p53 and represses its transcriptional activity. This viral gene product further inhibits the ability of p53 to induce cell death. We propose that LANA contributes to viral persistence and oncogenesis in KS through its ability to promote cell survival by altering p53 function.
TL;DR: It is reported that at twice the normal number of population doublings, telomerase-expressing human skin fibroblasts and retinal pigment epithelial cells (RPE-hTERT) retain normal growth control in response to serum deprivation, high cell density, G1 or G2 phase blockers and spindle inhibitors.
Abstract: Expression of the human telomerase catalytic component, hTERT, in normal human somatic cells can reconstitute telomerase activity and extend their replicative lifespan We report here that at twice the normal number of population doublings, telomerase-expressing human skin fibroblasts (BJ-hTERT) and retinal pigment epithelial cells (RPE-hTERT) retain normal growth control in response to serum deprivation, high cell density, G1 or G2 phase blockers and spindle inhibitors In addition, we observed no cell growth in soft agar and detected no tumour formation in vivo Thus, we find that telomerase expression in normal cells does not appear to induce changes associated with a malignant phenotype
TL;DR: It is found that a mouse 38K protein (p38) encoded by the Jab1 gene interacts specifically with p27Kip1 and it is shown that overexpression of p38 in mammalian cells causes the translocation of p27kip1 from the nucleus to the cytoplasm, decreasing the amount of p 27Kip 1 in the cell by accelerating its degradation.
Abstract: The proliferation of mammalian cells is under strict control, and the cyclin-dependent-kinase inhibitory protein p27Kip1 is an essential participant in this regulation both in vitro and in vivo. Although mutations in p27Kip1 are rarely found in human tumours, reduced expression of the protein correlates well with poor survival among patients with breast or colorectal carcinomas, suggesting that disruption of the p27Kip1 regulatory mechanisms contributes to neoplasia. The abundance of p27Kip1 in the cell is determined either at or after translation, for example as a result of phosphorylation by cyclinE/Cdk2 complexes, degradation by the ubiquitin/proteasome pathway, sequestration by unknown Myc-inducible proteins, binding to cyclinD/Cdk4 complexes, or inactivation by the viral E1A oncoprotein. We have found that a mouse 38K protein (p38) encoded by the Jab1 gene interacts specifically with p27Kip1 and show here that overexpression of p38 in mammalian cells causes the translocation of p27Kip1 from the nucleus to the cytoplasm, decreasing the amount of p27Kip1 in the cell by accelerating its degradation. Ectopic expression of p38 in mouse fibroblasts partially overcomes p27Kip1-mediated arrest in the G1 phase of the cell cycle and markedly reduces their dependence on serum. Our findings indicate that p38 functions as a negative regulator of p27Kip1 by promoting its degradation.
TL;DR: The results indicate that dMyc links patterning signals to cell division by regulating primary targets involved in cellular growth and metabolism.
TL;DR: Results suggest that the angiogenic activity attributed to VEGF may be due in part to its ability to enhance endothelial cell survival by inducing expression of the anti-apoptotic protein Bcl-2.
Abstract: Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and permeability factor that is potently angiogenic in vivo. We report here studies that suggest that VEGF potentiates angiogenesis in vivo and prolongs the survival of human dermal microvascular endothelial cells (HDMECs) in vitro by inducing expression of the anti-apoptotic protein Bcl-2. Growth-factor-enriched and serum-deficient cultures of HDMECs grown on collagen type I gels with VEGF exhibited a 4-fold and a 1.6-fold reduction, respectively, in the proportion of apoptotic cells. Enhanced HDMEC survival was associated with a dose-dependent increase in Bcl-2 expression and a decrease in the expression of the processed forms of the cysteine protease caspase-3. Cultures of HDMECs transduced with and overexpressing Bcl-2 and deprived of growth factors showed enhanced protection from apoptosis and exhibited a twofold increase in cell number and a fourfold increase in the number of capillary-like sprouts. HDMECs overexpressing Bcl-2 when incorporated into polylactic acid sponges and implanted into SCID mice exhibited a sustained fivefold increase in the number of microvessels and a fourfold decrease in the number of apoptotic cells when examined 7 and 14 days later. These results suggest that the angiogenic activity attributed to VEGF may be due in part to its ability to enhance endothelial cell survival by inducing expression of Bcl-2.
TL;DR: C‐Jun protects cells from UV‐induced cell death and cooperates with NF‐κB to prevent apoptosis induced by tumor necrosis factor alpha (TNFα), and shows that different extracellular stimuli can target c‐Jun by distinct biochemical mechanisms.
Abstract: c-Jun is a component of the transcription factor AP-1, which is activated by a wide variety of extracellular stimuli. The regulation of c-Jun is complex and involves both increases in the levels of c-Jun protein as well as phosphorylation of specific serines (63 and 73) by Jun N-terminal kinase (JNK). We have used fibroblasts derived from c-Jun null embryos to define the role of c-Jun in two separate processes: cell growth and apoptosis. We show that in fibroblasts, c-Jun is required for progression through the G1 phase of the cell cycle; c-Jun-mediated G1 progression occurs by a mechanism that involves direct transcriptional control of the cyclin D1 gene, establishing a molecular link between growth factor signaling and cell cycle regulators. In addition, c-Jun protects cells from UV-induced cell death and cooperates with NF-kappaB to prevent apoptosis induced by tumor necrosis factor alpha (TNFalpha). c-Jun mediated G1 progression is independent of phosphorylation of serines 63/73; however, protection from apoptosis in response to UV, a potent inducer of JNK/SAP kinase activity, requires serines 63/73. The results reveal critical roles for c-Jun in two different cellular processes and show that different extracellular stimuli can target c-Jun by distinct biochemical mechanisms.
TL;DR: The p53 tumor suppressor protein plays a crucial role in regulating cell growth following exposure to various stress stimuli p53 induces either growth arrest, which prevents the replication of damaged DNA, or programmed cell death (apoptosis), which is important for eliminating defective cells as discussed by the authors.
Abstract: The p53 tumor suppressor protein plays a crucial role in regulating cell growth following exposure to various stress stimuli p53 induces either growth arrest, which prevents the replication of damaged DNA, or programmed cell death (apoptosis), which is important for eliminating defective cells Whether the cell enters growth arrest or undergoes apoptosis, depends on the final integration of incoming signals with antagonistic effects on cell growth Many factors affect the cellular response to activated p53 These include the cell type, the oncogenic status of the cell with emphasis on the Rb/E2F balance, the extracellular growth and survival stimuli, the intensity of the stress signals, the level of p53 expression and the interaction of p53 with specific proteins p53 is regulated both at the levels of protein stability and biochemical activities This complex regulation is mediated by a range of viral and cellular proteins This review discusses this intriguing complexity which affects the cell response to p53 activation
Journal Article•
TL;DR: SLP induction in breast carcinoma cells treated with retinoids in vitro or in vivo was found to correlate with permanent growth inhibition under the conditions of minimal cytotoxicity, suggesting that this response may be particularly important for the antiproliferative effect of differentiating agents.
Abstract: Exposure of human tumor cell lines to different chemotherapeutic drugs, ionizing radiation, and differentiating agents induced morphological, enzymatic, and ploidy changes resembling replicative senescence of normal cells. Moderate doses of doxorubicin induced this senescence-like phenotype (SLP) in 11 of 14 tested cell lines derived from different types of human solid tumors, including all of the lines with wild-type p53 and half of p53-mutated cell lines. SLP induction seemed to be independent from mitotic cell death, the other major effect of drug treatment. Among cells that survived drug exposure, SLP markers distinguished those cells that became terminally growth-arrested within a small number of cell divisions from the cells that recovered and resumed proliferation. SLP induction in breast carcinoma cells treated with retinoids in vitro or in vivo was found to correlate with permanent growth inhibition under the conditions of minimal cytotoxicity, suggesting that this response may be particularly important for the antiproliferative effect of differentiating agents. The senescence-like program of terminal proliferation arrest may provide an important determinant of treatment outcome and a target for augmentation in cancer therapy.
TL;DR: Flow cytometric and cytogenetic analysis showed that this cell line represents one hyper DNA-diploid stem line with two clonal, evolved cytogenetics sublines, and like the parental C WR22 and CWR22R xenografts, thiscell line expresses prostate specific antigen.
Abstract: A cell line has been derived from a human prostatic carcinoma xenograft, CWR22R. This represents one of very few available cell lines representative of this disease. The cell line is derived from a xenograft that was serially propagated in mice after castration-induced regression and relapse of the parental, androgen-dependent CWR22 xenograft. Flow cytometric and cytogenetic analysis showed that this cell line represents one hyper DNA-diploid stem line with two clonal, evolved cytogenetic sublines. The basic karyotype is close to that of the grandparent xenograft, CWR22, and is relatively simple with 50 chromosomes. In nude mice, the line forms tumors with morphology similar to that of the xenografts, and like the parental CWR22 and CWR22R xenografts, this cell line expresses prostate specific antigen. Growth is weakly stimulated by dihydroxytestosterone and lysates are immunoreactive with androgen receptor antibody by Western blot analysis. Growth is stimulated by epidermal growth factor but is not inhibited by transforming growth factor-beta1.
TL;DR: Chronic hyperglycemia leads to β cell hypertrophy and loss of β cell differentiation that is correlated with changes in c-Myc and other key transcription factors, which could contribute to the profound derangement of insulin secretion in human diabetes.
TL;DR: Ascorbic acid enhanced the antilymphoma effect of As2O3 in vivo without additional toxicity, and may provide a novel therapy for lymphoma.
TL;DR: It is shown that STAT5 has pleiotropic functions regulating cell proliferation, differentiation and apoptosis in an IL‐3‐dependent Ba/F3 cell line, and suggests that a single transcription factor regulates cell fate by varying the intensity and duration of the expression of a set of target genes.
Abstract: Signal transducers and activators of transcription (STATs) play key roles in growth factor‐mediated intracellular signal transduction. In the present study using a constitutively active STAT5 mutant, we show that STAT5 has pleiotropic functions regulating cell proliferation, differentiation and apoptosis in an IL‐3‐dependent Ba/F3 cell line. The mutant STAT5 possessed constitutive tyrosine phosphorylation and DNA binding activity, induced expression of bcl‐xL and pim‐1 in the absence of IL‐3 in Ba/F3 cells, and rendered Ba/F3 cells factor‐independent. Unexpectedly, IL‐3 treatment of the factor‐independent Ba/F3 cells expressing the constitutively active STAT5 resulted in apoptosis within 24 h, or differentiation followed by cell death. In these cells, mRNA expression of growth inhibitory genes downstream of STAT5 such as CIS, JAB/SOCS‐1/SSI‐1, and p21 WAF1/Cip1 was highly induced, correlating with prolonged hyper‐phosphorylation of the mutant STAT5 after IL‐3 stimulation. Of the STAT5‐regulated genes, we found that constitutive expression of JAB/SOCS‐1/SSI‐1 was sufficient to induce apoptosis of Ba/F3 cells, while p21 WAF1/Cip1 could induce differentiation of these cells. In contrast, constitutive expression of pim‐1 was sufficient to induce IL‐3‐independent growth of Ba/F3 cells. These findings suggest that a single transcription factor regulates cell fate by varying the intensity and duration of the expression of a set of target genes.
TL;DR: Flavonoids of the flavone, flavonol, flavanone, and isoflavone classes possess antiproliferative effects in different cancer cell lines.
Abstract: Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Their proposed protective role in tumor development may prevail especially in the intestinal tract due to direct exposure of intestinal epithelia to these dietary ingredients. We have screened more than 30 flavonoids for their effects on cell proliferation and potential cytotoxicity in the human colon cancer cell lines Caco-2, displaying features of small intestinal epithelial cells, and HT-29, resembling colonic crypt cells. In addition, for selected compounds we assessed whether they induce apoptosis by determining caspase-3 activation. Studies on the dose dependent effects of the flavonoids showed antiproliferative activity of all compounds with EC50 values ranging between 39.7 ± 2.3 μM (baicalein) and 203.6 ± 15.5 μM (diosmin). In almost all cases, growth inhibition by the flavonoids occured in the absence of cytotoxicity. There was no obvious structure-activity relationship in the antiproliferative effects either on basis of the subclasses (i.e., isoflavones, flavones, flavonols, flavanones) or with respect to kind or position of substituents within a class.
TL;DR: There is overwhelming evidence from in vivo and cell culture studies that induction of the transforming growth factor-beta (TGF-beta) system mediates the actions of high ambient glucose and that this system is pivotal for the hypertrophy of mesangial and tubular cells.
TL;DR: This work has shown that mammalian fibroblasts are not able to adapt but instead enter a permanently growth‐arrested state in which they appear to perform most normal cell functions but never divide again, a new paradigm of cellular oxidative stress responses.
Abstract: Proliferating mammalian cells exhibit a broad spectrum of responses to oxidative stress, depending on the stress level encountered. Very low levels of hydrogen peroxide, e.g., 3 to 15 microM, or 0.1 to 0.5 micromol/10(7) cells, cause a significant mitogenic response, 25% to 45 % growth stimulation. Greater concentrations of H2O2, 120 to 150 microM, or 2 to 5 micromol/10(7) cells, cause a temporary growth arrest that appears to protect cells from excess energy use and DNA damage. After 4-6 h of temporary growth arrest, many cells will exhibit up to a 40-fold transient adaptive response in which genes for oxidant protection and damage repair are preferentially expressed. After 18 h of H2O2 adaptation (including the 4-6 h of temporary growth arrest) cells exhibit maximal protection against oxidative stress. The H2O2 originally added is metabolized within 30-40 min, and if no more is added the cells will gradually de-adapt, so that by 36 h after the initial H2O2 stimulus they have returned to their original level of H2O2 sensitivity. At H2O2 concentrations of 250 to 400 microM, or 9 to 14 micromol/10(7) cells, mammalian fibroblasts are not able to adapt but instead enter a permanently growth-arrested state in which they appear to perform most normal cell functions but never divide again. This state of permanent growth arrest has often been confused with cell death in toxicity studies relying solely on cell proliferation assays as measures of viability. If the oxidative stress level is further increased to 0.5 to 1.0 mM H2O2, or 15 to 30 micromol/10(7) cells, apoptosis results. This oxidative stress-induced apoptosis involves nuclear condensation, loss of mitochondrial transmembrane potential, degradation/down-regulation of mitochondrial mRNAs and rRNAs, and degradation/laddering of both nuclear and mitochondrial DNA. At very high H2O2 concentrations of 5.0 to 10.0 mM, or 150 to 300 micromol/10(7) cells and above, cell membranes disintegrate, proteins and nucleic acids denature, and necrosis swiftly follows. Cultured cells grown in 20% oxygen are essentially preadapted or preselected to survive under conditions of oxidative stress. If cells are instead grown in 3% oxygen, much closer to physiological cellular levels, they are more sensitive to an oxidative challenge but exhibit far less accumulated oxidant damage. This broad spectrum of cellular responses to oxidant stress, depending on the amount of oxidant applied and the concentration of oxygen in the cell culture system, provides for a new paradigm of cellular oxidative stress responses.
TL;DR: The results indicate that Pim-family proteins play crucial roles in gp130-mediated cell proliferation and explain the synergy between Pim and c-Myc proteins in celliferation and lymphomagenesis.
TL;DR: A major recent advance is the identification of a subfamily of heptahelical receptors for LPA and S1P that induce profound cytoskeletal changes through Rho-mediated signaling pathways.
TL;DR: It is shown that transfection of EAG into mammalian cells confers a transformed phenotype, and inhibition of E AG expression in several somatic cancer cell lines causes a significant reduction of cell proliferation.
Abstract: We have investigated the possible implication of the cell cycle‐regulated K+ channel ether a go‐go (EAG) in cell proliferation and transformation. We show that transfection of EAG into mammalian cells confers a transformed phenotype. In addition, human EAG mRNA is detected in several somatic cancer cell lines, despite being preferentially expressed in brain among normal tissues. Inhibition of EAG expression in several of these cancer cell lines causes a significant reduction of cell proliferation. Moreover, the expression of EAG favours tumour progression when transfected cells are injected into immune‐depressed mice. These data provide evidence for the oncogenic potential of EAG.
Journal Article•
TL;DR: The findings indicate that COX-2 up-regulation is a frequent event in pancreatic cancers and suggest that nonsteroidal anti-inflammatory drugs may be useful in the chemoprevention and therapy of pancreatic carcinoma.
Abstract: Cyclooxygenase (COX)-2 mRNA and protein expression were found to be frequently elevated in human pancreatic adenocarcinomas and cell lines derived from such tumors. Immunohistochemistry demonstrated cytoplasmic COX-2 expression in 14 of 21 (67%) pancreatic carcinomas. The level of COX-2 mRNA was found to be elevated in carcinomas, relative to histologically normal pancreas from a healthy individual, as assessed by reverse transcription-PCR. COX-2 protein expression was detected by the Western blot assay in three of five pancreatic carcinoma cell lines (BxPC-3, Capan-1, and MDAPanc-3), whereas COX-1 protein was detected in two of the five cell lines (BxPC-3 and Capan-1). Increased levels of COX-2 mRNA were found in four of five cell lines, and only in PANC-1 cells was the low level of transcript comparable to that in the normal pancreas. The level of COX-2 mRNA was positively correlated with the differentiation status of the tumor of origin for each cell line, COX-2 protein expression was up-regulated by epidermal growth factor when the cells were grown in absence of serum. Finally, two nonsteroidal anti-inflammatory drugs, sulindac sulfide and NS398, produced a dose-dependent inhibition of cell proliferation in all pancreatic cell lines tested. No correlation was found between the level of COX-2 or COX-1 expression and the extent of growth inhibition. Treatment of BxPC-3 cells with sulindac sulfide and NS398 resulted in an induction of COX-2 expression. Our findings indicate that COX-2 up-regulation is a frequent event in pancreatic cancers and suggest that nonsteroidal anti-inflammatory drugs may be useful in the chemoprevention and therapy of pancreatic carcinoma.