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Cyclin D3 (cyclin + d3)
Terms modified by Cyclin D3 Selected AbstractsInduction of G2/M phase arrest and apoptosis by a novel indoloquinoline derivative, IQDMA, in K562 cellsDRUG DEVELOPMENT RESEARCH, Issue 9 2006Yi-Hsiung Lin Abstract The indoloquinoline, IQDMA (N,-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine), was identified as a novel antineoplastic agent with broad spectrum of antitumor activities against several human cancer cells. IQDMA-induced G2/M arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitors (CDKIs), p21 and p27, and down-regulation of Cdk1and Cdk2. IQDMA had no effect on the levels of cyclin A, cyclin B1, cyclin D3, or Cdc25C. IQDMA also increased apoptosis, as characterized by apoptotic body formation, increase of the sub G1 population and poly (ADP-ribose) polymerase (PARP) cleavage. Further mechanistic analysis demonstrated that IQDMA upregulated FasL protein expression, and kinetic studies showed the sequential activation of caspases-8, -3, and -9. Both caspase-8 and caspase-3 inhibitors, but not a caspase-9-specific inhibitor, suppressed IQDMA-induced cell death. These molecular alterations provide an insight into IQDMA-caused growth inhibition, G2/M arrest, and apoptotic death of K562 cells. Drug Dev. Res. 67:743,751, 2006. © 2006 Wiley-Liss, Inc. [source] Cell-cycle deregulation in BALB/c 3T3 cells transformed by 1,2-dibromoethane and folpet pesticidesENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 5 2003Maria Alessandra Santucci Abstract The cell-transforming potential of 1,2-dibromoethane and folpet, two widely used agricultural pesticides that are potential sources of environmental pollution, has been previously ascribed to their promoting activity. In this study, we investigated whether BALB/c 3T3 transformation by these chemicals was associated with the deregulation of signals involved in cell-cycle progression and in cell-cycle checkpoint induction. We found that two BALB/c 3T3 cell clones transformed by in vitro medium-term (8-week) exposure to the carcinogens had a constitutive acceleration of cell transition from G1 to S phase and an abrogation of the radiation-induced G1/S checkpoint. These events involved multiple signals; in particular, the inhibitors of cyclin/cyclin-dependent kinase complexes p21 and p27 were significantly down-modulated and the positive regulators of cell-cycle progression cyclin D3 and E were up-modulated. As anticipated for cells where the G1/S checkpoint was abrogated, the transformed cells exhibited a significant reinforcement of the radiation-induced G2/M checkpoint, the only checkpoint remaining to protect genomic integrity. However, cyclin A1 and B1 coexpression and cyclin A1 overexpression were found despite the G2 arrest in irradiated cells and these signals likely attenuate the G2/M checkpoint. These alterations to normal cell cycling may promote the emergence of both numerical and structural chromosomal abnormalities and their tolerance. Such a condition could play a key role in neoplastic transformation and be crucial in tumor progression. Furthermore, cyclin A1 overexpression may play an autonomous role in the neoplastic transformation of BALB/c 3T3 cells, as it does in other cell types of mesenchymal origin. Environ. Mol. Mutagen. 41:315,321, 2003. © 2003 Wiley-Liss, Inc. [source] CD34+ cells derived from fetal liver contained a high proportion of immature megakaryocytic progenitor cellsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2000Dong-Chu Ma Abstract: Endoreplication and maturation of the megakaryocyte (MK) may be retarded or delayed during ontogenesis. In this study, CD34+ cells were isolated from both human fetal liver and adult bone marrow and incubated with thrombopoietin (TPO). The cell number, morphological characteristics, platelet-associated antigen phenotype, maturation stage and DNA ploidy of CD41+cells were examined from day 0 to day 12 in culture. 1) TPO stimulated the proliferation of fetal liver (FL)-derived CD34+ cells with a mean 73.14-fold increase of CD41+ cells after 12 d in culture. Adult BM-derived CD34+ cells increased only slightly, with a mean 8.18-fold increase of CD41+ cells. 2) Although the membrane phenotype of both FL CD34+ -derived MKs and BM CD34+ -derived MKs analyzed with CD41a, CD42a, CD61 and CD34 were similar, all FL CD34+ -derived MKs were in maturation stage I and II and in low ploidy (<4N) class. By comparison, BM CD34+ MKs possessed 15% MKs in maturation stage III and IV and with 23% MKs in high ploidy class (>4N). 3) Most of cultured FL-derived CD34+ cells did not have a well developed demarcation system (DM) and numerous ,-granules after 12 d incubation. von Willebrand factor (vWF) appeared earlier on the cultured BM-derived CD34+ cells than on FL-derived CD34+ cells. 4) The expression of both cyclin E and cyclin B1 progressively increased in FL CD34+cells induced by TPO during 12 d in culture. 5) The expression of cyclin D1 gradually decreased in FL CD34+cells induced by TPO over 12 d incubation. 6) Immunocytochemical analysis showed that cyclin D3 was detected only in cytoplasm of cultured FL-derived CD34+ cells, whereas in both cytoplasm and nuclei of cultured BM-derived CD34+ cells. These data suggest that FL-derived CD34+ cells contain a high proportion of immature megakaryocytic progenitor cells. It further suggests that TPO can push these progenitor cells into proliferation by upregulating the expression of cyclins B1 and E, and drive a high proportion of cells into megakaryocytic lineage. [source] Heregulin and forskolin-induced cyclin D3 expression in Schwann cells: Role of a CCAAT promoter element and CCAAT enhancer binding proteinGLIA, Issue 3 2004Luis Fuentealba Abstract Heregulin, a polypeptide growth factor, and forskolin, an adenylyl cyclase activator, synergistically stimulate expression of cyclin D3 and cell division in Schwann cells. Heregulin induces expression in Schwann cells of a luciferase reporter gene linked to the cyclin D3 promoter. Forskolin markedly augments reporter expression in the presence of heregulin. Deletion analysis identified several promoter sites that contribute to high-level reporter expression in heregulin- and forskolin-treated Schwann cells. A promoter fragment that contains 103 bp of 5,-flanking sequence produced significant reporter expression in heregulin- and forskolin-stimulated cells. Deletion of a consensus CCAAT site within this promoter fragment caused a nearly complete loss of reporter expression. Similar results were obtained when CCAAT site mutations were introduced into the promoter. Heregulin and forskolin increased steady-state levels of CCAAT/enhancer binding protein-, (C/EBP,) in Schwann cells. Mobility shift assays identified proteins in Schwann cell nuclear extracts that formed stable complexes with the cyclin D3 CCAAT promoter element and were disrupted by anti-C/EBP, antibody. Transfection of Schwann cells with C/EBP, cDNA increased cyclin D3 reporter expression. In contrast to these results, mutation of a cAMP response element in the cyclin D3 promoter had only a modest effect on heregulin- and forskolin-stimulated reporter expression. These findings demonstrate that C/EBP, plays a key role in the heregulin and cAMP-dependent regulation of cyclin D3 expression in Schwann cells. © 2003 Wiley-Liss, Inc. [source] Pathogenesis of Helicobacter pylori InfectionHELICOBACTER, Issue 2004Paul Hofman ABSTRACT Research in the last year has provided new insights into the function of the the cag -associated type IV secretion system and the vacuolating toxin VacA. A quite new aspect was disclosed by the finding that Helicobacter pylori in Mongolian gerbils colonizes a very distinct topology in the gastric mucous layer, obviously providing optimal conditions for long-term survival. Further research activities focused on H. pylori ammonia and metal metabolism as well as on bacterial stress defence mechanisms. Differential expression of approximately 7% of the bacterial genome was found at low pH suggesting that H. pylori has evolved a multitude of acid-adaptive mechanisms. VacA was shown to interrupt phagosome maturation in macrophage cell lines as well as to modulate and interfere with T lymphocyte immunological functions. Gastric mucosa as well as the H. pylori -infected epithelial cell line AGS strongly express IL-8 receptor A and B, which might contribute to the augmentation of the inflammatory response. Accumulating evidence implicates genetic variation in the inflammatory response to H. pylori in the etiology of the increased risk of gastric cancer after H. pylori infection. The chronic imbalance between apoptosis and cell proliferation is the first step of gastric carcinogenesis. In this regard, it was demonstrated that coexpression of two H. pylori proteins, CagA and HspB, in AGS cells, caused an increase in E2F transcription factor, cyclin D3, and phosphorylated retinoblastoma protein. Taken together, we now have a better understanding of the role of different virulence factors of H. pylori. There is still a lot to be learned, but the promising discoveries summarized here, demonstrate that the investigation of the bacterial survival strategies will give novel insights into pathogenesis and disease development. [source] Respiratory chain deficiency slows down cell-cycle progression via reduced ROS generation and is associated with a reduction of p21CIP1/WAF1JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2006Matthias Schauen We have used HeLa cells without mitochondrial DNA (,0 -cells) and transient ,0 -phenocopies, obtained from wild-type cells by short-term treatment with ethidium bromide, to analyze how the absence of a functional mitochondrial respiratory chain slows down proliferation. We ruled out an energetic problem (ATP/ADP content) as well as defective synthesis of pyrimidine, iron-sulfur clusters or heme as important causes for the proliferative defect. Flow cytometric analysis revealed that reactive oxygen species were reduced in ,0 -cells and in ,0 -phenocopies, and that, quite unusually, all stages of the cell cycle were slowed down. Specific quenching of mitochondrial ROS with the ubiquinone analog MitoQ also resulted in slower growth. Some important cell-cycle regulators were reduced in ,0 -cells: cyclin D3, cdk6, p18INK4C, p27KIP1, and p21CIP1/WAF1. In the ,0 -phenocopies, the expression pattern did not fully duplicate the complex response observed in ,0 -cells, and mainly p21CIP1/WAF1 was downregulated. Activities of the growth regulatory PKB/Akt and MAPK/ERK-signaling pathways did not correlate with proliferation rates of ,0 -cells and ,0 -phenocopies. Our study demonstrates that loss of a functional mitochondrial electron transport chain inhibits cell-cycle progression, and we postulate that this occurs through the decreased concentration of reactive oxygen species, leading to downregulation of p21CIP1/WAF1. J. Cell. Physiol. 209: 103,112, 2006. © 2006 Wiley-Liss, Inc. [source] Antiproliferative action of valproate is associated with aberrant expression and nuclear translocation of cyclin D3 during the C6 glioma G1 phaseJOURNAL OF NEUROCHEMISTRY, Issue 1 2002Christopher L. Bacon Abstract Cell cycle progression is tightly regulated by cyclins, cyclin-dependent kinases (cdks) and related inhibitory phophatases. Here, we employed mitotic selection to synchronize the C6 glioma cell cycle at the start of the G1 phase and mapped the temporal regulation of selected cyclins, cdks and inhibitory proteins throughout the 12 h of G1 by immunoblot analysis. The D-type cyclins, D3 and D1, were differentially expressed during the C6 glioma G1 phase. Cyclin D1 was up-regulated in the mid-G1 phase (4,6 h) while cyclin D3 expression emerged only in late G1 (9,12 h). The influence of the anticonvulsant agent valproic acid (VPA) on expression of cyclins and related proteins was determined, since its teratogenic potency has been linked to cell cycle arrest in the mid-G1 phase. Exposure of C6 glioma to VPA induced a marked up-regulation of cyclin D3 and decreased expression of the proliferating cell nuclear antigen. In synchronized cell populations, increased expression of cyclin D3 by VPA was detected in the mid-G1 phase (3,5 h). Immunocytochemical localization demonstrated rapid intracellular translocation of cyclin D3 to the nucleus following VPA exposure, suggesting that VPA-induced cell cycle arrest may be mediated by precocious activation of cyclin D3 in the G1 phase. [source] Alsterpaullone, a novel cyclin-dependent kinase inhibitor, induces apoptosis by activation of caspase-9 due to perturbation in mitochondrial membrane potential,MOLECULAR CARCINOGENESIS, Issue 4 2003Tyler Lahusen Abstract The majority of human neoplasms have aberrations in the retinoblastoma pathway due to hyperactivation of cyclin-dependent kinases (CDK). Based on this observation, novel small molecules, such as flavopiridol and UCN-01, are being developed and are currently being tested in the clinic. Efforts to develop CDK modulators led us to the discovery of a novel class of CDK inhibitors, the paullones [Cancer Res 1999;59:2566]. Initial studies demonstrated that paullones inhibit CDKs in vitro, thereby blocking cell-cycle progression. However, the exact mechanism for the antiproliferative effects of paullones was never explored. In this report, we demonstrate for the first time that the most potent paullone, alsterpaullone (Alp), induced apoptosis and promoted loss in clonogenicity in the Jurkat cell line. Alp caused early activation of both caspase-8 and -9, leading to cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, apoptosis by Alp was not associated with loss in anti-apoptotic proteins such as XIAP or BCL-XL. Pre-incubation with cell-permeable inhibitors z-Asp(OMe)-Glu(OMe)-Val-Asp(Ome)-fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (ZVAD) blocked Alp-induced apoptosis. Moreover, the general caspase inhibitor ZVAD blocked the cleavage and activation of most caspases tested except caspase-9. Studies of mitochondrial membrane potential also demonstrated that Alp is able to disrupt mitochondrial potential in the presence of ZVAD, suggesting that the activation of caspase-9 by Alp follows mitochondrial perturbation. Pre-incubation of Jurkat cells with ZVAD did not prevent the depletion of cyclin D3, loss of CDK, or cell-cycle arrest by Alp. In summary, these experiments suggest that Alp activates caspase-9 via mitochondrial perturbation. Active caspase-9 cleaves and activates caspase-8 and caspase-3, leading to apoptosis. In the presence of the general caspase inhibitor ZVAD, the cell-cycle effects of Alp are unaltered while apoptosis is blocked, suggesting that the CDK effects of Alp are not sufficient for Alp-induced apoptosis. Additional studies with paullones are warranted to further characterize their preclinical effects and to explore their potential use in the clinical setting. Published 2003 Wiley-Liss, Inc. [source] | |||||||||||||