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Joelle Sobczakthepot - One of the best experts on this subject based on the ideXlab platform.
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centrosome overduplication increased ploidy and transformation in cells expressing endoplasmic reticulum associated Cyclin A2
Oncogene, 2002Co-Authors: Jamila Faivre, Helene Mouly, Christian Bréchot, Joelle Sobczakthepot, Marie Frankvaillant, Robert Poulhe, Catherine JessusAbstract:Cyclin A2 is predominantly, but not exclusively, localized in the nucleus from G1/S transition onwards. It is degraded when cells enter mitosis after nuclear envelope breakdown. We previously showed that a fusion protein (S2A) between the hepatitis B virus (HBV) surface antigen protein and a non-degradable fragment of human Cyclin A2 (Delta152) resides in the endoplasmic reticulum membranes, escapes degradation and transforms normal rat fibroblasts. The present study investigates whether cytoplasmic Cyclin A2 may play a role in oncogenesis. We show that the sequestration of non-degradable Cyclin A2-Delta152 by a cellular ER targeting domain (PRL-A2) leads to cell transformation when coexpressed with activated Ha-ras. REF52 cells constitutively expressing PRL-A2 are found to have a high incidence of multinucleate giant cells, polyploidy and abnormal centrosome numbers, giving rise to the nucleation of multipolar spindles. Injection of these cells into athymic nude mice causes tumors, even in the absence of a cooperating Ha-ras oncogene. These results demonstrate that, independently of any viral context, an intracellular redistribution of non-degradable Cyclin A2 is capable of deregulating the normal cell cycle to the point where it promotes aneuploidy and cancer.
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membrane anchored Cyclin A2 triggers cdc2 activation in xenopus oocyte
FEBS Letters, 2001Co-Authors: Jamila Faivre, Helene Mouly, Christian Bréchot, Joelle Sobczakthepot, Marie Frankvaillant, Robert Poulhe, Catherine JessusAbstract:In Xenopus oocyte, the formation of complexes between neosynthesized Cyclins and Cdc2 contributes to Cdc2 kinase activation that triggers meiotic divisions. It has been proposed that cytoplasmic membranes could be involved in this process. To investigate this possibility, we have injected in the oocyte two undegradable human Cyclin A2 mutants anchored to the endoplasmic reticulum (ER) membrane. They encode fusion proteins between the truncated Cyclin A2-v152 and a viral or cellular ER-targeting domain. We show that both mutants are fully functional as mitotic Cyclins when expressed in Xenopus oocytes, bind Cdc2 and activate M-phase promoting factor. fl 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.
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early development of mouse embryos null mutant for the Cyclin A2 gene occurs in the absence of maternally derived Cyclin A2 gene products
Developmental Biology, 2000Co-Authors: Nicola Winston, Christian Bréchot, Florence Bourgainguglielmetti, Maria A Ciemerych, Jacek Z Kubiak, Catherine Senamaudbeaufort, Mark Carrington, Joelle SobczakthepotAbstract:Progression through the mammalian cell cycle is regulated by the sequential activation and inactivation of the Cyclin-dependent kinases. In adult cells, Cyclin A2-dependent kinases are required for entry into S and M phases, completion of S phase, and centrosome duplication. However, mouse embryos lacking the Cyclin A2 gene nonetheless complete preimplantation development, but die soon after implantation. In this report, we investigated whether a contribution of maternal Cyclin A2 mRNA and protein to early embryonic cell cycles might explain these conflicting observations. Our data show that a maternal stock of Cyclin A2 mRNA is present in the oocyte and persists after fertilization until the second mitotic cell cycle, when it is degraded to undetectable levels coincident with transcriptional activation of the zygotic genome. A portion of maternally derived Cyclin A2 protein is stable during the first mitosis and persists in the cytoplasm, but is completely degraded at the second mitosis. The ability of Cyclin A2-null mutants to develop normally from the four-cell to the postimplantation stage in the absence of detectable Cyclin A2 gene product indicates therefore that Cyclin A2 is dispensable for cellular progression during the preimplantation nongrowth period of mouse embryo development.
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camp dependent positive control of Cyclin A2 expression during g1 s transition in primary hepatocytes
Biochemical and Biophysical Research Communications, 1999Co-Authors: Chantal Desdouets, Christian Bréchot, Catherine Senamaudbeaufort, G H Thoresen, Thoralf Christoffersen, Joelle SobczakthepotAbstract:cAMP positively and negatively regulates hepatocyte proliferation but its molecular targets are still unknown. Cyclin A2 is a major regulator of the cell cycle progression and its synthesis is required for progression to S phase. We have investigated whether Cyclin A2 and Cyclin A2-associated kinase might be one of the targets for the cAMP transduction pathway during progression of hepatocytes through G1 and G1/S. We show that stimulation of primary cultured hepatocytes by glucagon differentially modulated the expression of G1/S Cyclins. Glucagon indeed upregulated Cyclin A2 and Cyclin A2-associated kinase while Cyclin E-associated kinase was unmodified. In conclusion, our study identifies Cyclin A2 as an important effector of the cAMP transduction network during hepatocyte proliferation.
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delayed early embryonic lethality following disruption of the murine Cyclin A2 gene
Nature Genetics, 1997Co-Authors: Martin Murphy, Christian Bréchot, Nicola Winston, Catherine Senamaudbeaufort, Mark Carrington, Michal Kubelka, Mariegeorges Stinnakre, Claire Sweeney, Joelle SobczakthepotAbstract:In higher eukaryotes, cell cycle progression is controlled by Cyclin dependent kinases (Cdks) complexed with Cyclins. A-type Cyclins are involved at both G1/S and G2/M transitions of the cell cycle. Cyclin A2 activates cdc2 (Cdk1) on passage into mitosis and Cdk2 at the G1/S transition. Antisense constructs, or antibodies directed against Cyclin A2 block cultured mammalian cells at both of these transitions. In contrast, overexpression of Cyclin A2 appears to advance S phase entry and confer anchorage-independent growth, and can lead to apoptosis. A second A-type Cyclin, Cyclin A1 has been described recently which, in the mouse, is expressed in germ cells but not somatic tissues. To address the possible redundancy between different Cyclins in vivo and also the control of early embryonic cell cycles, we undertook the targeted deletion of the murine Cyclin A2 gene. The homozygous null mutant is embryonically lethal, demonstrating that the Cyclin A2 gene is essential. Surprisingly, homozygous null mutant embryos develop normally until post-implantation, around day 5.5 p.c. This observation may be explained by the persistence of a maternal pool of Cyclin A2 protein until at least the blastocyst stage, or an unexpected role for Cyclin A1 during early embryo development.
Jean-marie Blanchard - One of the best experts on this subject based on the ideXlab platform.
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Foci of Cyclin A2 interact with actin and RhoA in mitosis
Scientific Reports, 2016Co-Authors: Abdelhalim Loukil, Fanny Izard, Mariya Georgieva, Shaereh Mashayekhan, Jean-marie Blanchard, Andrea Parmeggiani, Marion PeterAbstract:Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis depends primarily on the ubiquitin-proteasome system (UPS), while autophagy also contributes. However, a fraction of Cyclin A2 persists beyond metaphase. In this work, we focus on Cyclin A2-rich foci detected in mitosis by high resolution imaging and analyse their movements. We demonstrate that Cyclin A2 interacts with actin and RhoA during mitosis, and that Cyclin A2 depletion induces a dramatic decrease in active RhoA in mitosis. Our data suggest Cyclin A2 participation in RhoA activation in late mitosis.
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Cyclin A2 at the crossroads of cell cycle and cell invasion
World Journal of Biological Chemistry, 2015Co-Authors: Abdelhalim Loukil, Marion Peter, Nawal Bendris, Benedicte Lemmers, Caroline Cheung, Jean-marie BlanchardAbstract:Cyclin A2 is an essential regulator of the cell division cycle through the activation of kinases that participate to the regulation of S phase as well as the mitotic entry. However, whereas its degradation by the proteasome in mid mitosis was thought to be essential for mitosis to proceed, recent observations show that a small fraction of Cyclin A2 persists beyond metaphase and is degraded by autophagy. Its implication in the control of cytoskeletal dynamics and cell movement has unveiled its role in the modulation of RhoA activity. Since this GTPase is involved in both cell rounding early in mitosis and later, in the formation of the cleavage furrow, this suggests that Cyclin A2 is a novel actor in cytokinesis. Taken together, these data point to this Cyclin as a potential mediator of cell-niche interactions whose dysregulation could be taken as a hallmark of metastasis.
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Cyclin A2 modulates emt via β catenin and phospholipase c pathways
Carcinogenesis, 2015Co-Authors: Caroline Cheung, Jean-marie Blanchard, Nawal Bendris, Conception Paul, Abdallah Hamieh, Youssef Anouar, Michael Hahne, Benedicte LemmersAbstract:We have previously demonstrated that Cyclin A2 is involved in cytoskeletal dynamics, epithelial-mesenchymal transition (EMT) and metastasis. This phenotype was potentiated by activated oncogenic H-Ras. However, the mechanisms governing EMT in these cells have not yet been elucidated. Here, we dissected the pathways that are responsible for EMT in cells deficient for Cyclin A2. In Cyclin A2-depleted normal murine mammary gland (NMuMG) cells expressing RasV12, we found that β-catenin was liberated from the cell membrane and cell-cell junctions and underwent nuclear translocation and activation. Components of the canonical wingless (WNT) pathway, including WNT8b, WNT10a, WNT10b, frizzled 1 and 2 and TCF4 were upregulated at the messenger RNA and protein levels following Cyclin A2 depletion. However, suppression of the WNT pathway using the acetyltransferase porcupine inhibitor C59 did not reverse EMT whereas a dominant negative form of TCF4 as well as inhibition of phospholipase C using U73122 were able to do so. This suggests that a WNT-independent mechanism of β-catenin activation via phospholipase C is involved in the EMT induced by Cyclin A2 depletion. Our findings will broaden our knowledge on how Cyclin A2 contributes to EMT and metastasis.
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Cyclin A2 a novel regulator of emt
Cellular and Molecular Life Sciences, 2014Co-Authors: Nawal Bendris, Jean-marie Blanchard, Benedicte Lemmers, Caroline Cheung, Hon S Leong, John D Lewis, Ann F ChambersAbstract:Our previous work showed that Cyclin A2 deficiency promotes cell invasion in fibroblasts. Given that the majority of cancers emerge from epithelia, we explored novel functions for Cyclin A2 by depleting it in normal mammary epithelial cells. This caused an epithelial to mesenchymal transition (EMT) associated with loss of cell-to-cell contacts, decreased E-Cadherin expression and increased invasive properties characterized by a reciprocal regulation of RhoA and RhoC activities, where RhoA-decreased activity drove cell invasiveness and E-Cadherin delocalization, and RhoC-increased activity only supported cell motility. Phenotypes induced by Cyclin A2 deficiency were exacerbated upon oncogenic activated-Ras expression, which led to an increased expression of EMT-related transcriptional factors. Moreover, Cyclin A2-depleted cells exhibited stem cell-like properties and increased invasion in an in vivo avian embryo model. Our work supports a model where Cyclin A2 downregulation facilitates cancer cell EMT and metastatic dissemination.
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high resolution live cell imaging reveals novel Cyclin A2 degradation foci involving autophagy
Journal of Cell Science, 2014Co-Authors: Abdelhalim Loukil, Jean-marie Blanchard, Véronique Baldin, Cosette Rebouissou, Manuela Zonca, Olivier Coux, Martine Biardpiechaczyk, Marion PeterAbstract:Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis relies on the ubiquitin-proteasome system (UPS). Using high-resolution microscopic imaging, we find that Cyclin A2 persists beyond metaphase. Indeed, we identify a novel Cyclin-A2-containing compartment that forms dynamic foci. Forster (or fluorescence) resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM) analyses show that Cyclin A2 ubiquitylation takes place predominantly in these foci before spreading throughout the cell. Moreover, inhibition of autophagy in proliferating cells induces the stabilisation of a subset of Cyclin A2, whereas induction of autophagy accelerates the degradation of Cyclin A2, thus showing that autophagy is a novel regulator of Cyclin A2 degradation.
Christian Bréchot - One of the best experts on this subject based on the ideXlab platform.
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an intron retaining splice variant of human Cyclin A2 expressed in adult differentiated tissues induces a g1 s cell cycle arrest in vitro
PLOS ONE, 2012Co-Authors: Christian Bréchot, Jamila Faivre, Arata Honda, Yannick Valogne, Myriam Bou NaderAbstract:Background Human Cyclin A2 is a key regulator of S phase progression and entry into mitosis. Alternative splice variants of the G1 and mitotic Cyclins have been shown to interfere with full-length Cyclin functions to modulate cell cycle progression and are therefore likely to play a role in differentiation or oncogenesis. The alternative splicing of human Cyclin A2 has not yet been studied. Methodology/Principal Findings Sequence-specific primers were designed to amplify various exon–intron regions of Cyclin A2 mRNA in cell lines and human tissues. Intron retaining PCR products were cloned and sequenced and then overexpressed in HeLa cells. The subcellular localization of the splice variants was studied using confocal and time-lapse microscopy, and their impact on the cell cycle by flow cytometry, immunoblotting and histone H1 kinase activity. We found a splice variant of Cyclin A2 mRNA called A2V6 that partly retains Intron 6. The gene expression pattern of A2V6 mRNA in human tissues was noticeably different from that of wild-type Cyclin A2 (A2WT) mRNA. It was lower in proliferating fetal tissues and stronger in some differentiated adult tissues, especially, heart. In transfected HeLa cells, A2V6 localized exclusively in the cytoplasm whereas A2WT accumulated in the nucleus. We show that A2V6 induced a clear G1/S cell cycle arrest associated with a p21 and p27 upregulation and an inhibition of retinoblastoma protein phosphorylation. Like A2WT, A2V6 bound CDK2, but the A2V6/CDK2 complex did not phosphorylate histone H1. Conclusion/Significance This study has revealed that some highly differentiated human tissues express an intron-retaining Cyclin A2 mRNA that induced a G1/S block in vitro. Contrary to full-length Cyclin A2, which regulates cell proliferation, the A2V6 splice variant might play a role in regulating nondividing cell states such as terminal differentiation or senescence.
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centrosome overduplication increased ploidy and transformation in cells expressing endoplasmic reticulum associated Cyclin A2
Oncogene, 2002Co-Authors: Jamila Faivre, Helene Mouly, Christian Bréchot, Joelle Sobczakthepot, Marie Frankvaillant, Robert Poulhe, Catherine JessusAbstract:Cyclin A2 is predominantly, but not exclusively, localized in the nucleus from G1/S transition onwards. It is degraded when cells enter mitosis after nuclear envelope breakdown. We previously showed that a fusion protein (S2A) between the hepatitis B virus (HBV) surface antigen protein and a non-degradable fragment of human Cyclin A2 (Delta152) resides in the endoplasmic reticulum membranes, escapes degradation and transforms normal rat fibroblasts. The present study investigates whether cytoplasmic Cyclin A2 may play a role in oncogenesis. We show that the sequestration of non-degradable Cyclin A2-Delta152 by a cellular ER targeting domain (PRL-A2) leads to cell transformation when coexpressed with activated Ha-ras. REF52 cells constitutively expressing PRL-A2 are found to have a high incidence of multinucleate giant cells, polyploidy and abnormal centrosome numbers, giving rise to the nucleation of multipolar spindles. Injection of these cells into athymic nude mice causes tumors, even in the absence of a cooperating Ha-ras oncogene. These results demonstrate that, independently of any viral context, an intracellular redistribution of non-degradable Cyclin A2 is capable of deregulating the normal cell cycle to the point where it promotes aneuploidy and cancer.
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membrane anchored Cyclin A2 triggers cdc2 activation in xenopus oocyte
FEBS Letters, 2001Co-Authors: Jamila Faivre, Helene Mouly, Christian Bréchot, Joelle Sobczakthepot, Marie Frankvaillant, Robert Poulhe, Catherine JessusAbstract:In Xenopus oocyte, the formation of complexes between neosynthesized Cyclins and Cdc2 contributes to Cdc2 kinase activation that triggers meiotic divisions. It has been proposed that cytoplasmic membranes could be involved in this process. To investigate this possibility, we have injected in the oocyte two undegradable human Cyclin A2 mutants anchored to the endoplasmic reticulum (ER) membrane. They encode fusion proteins between the truncated Cyclin A2-v152 and a viral or cellular ER-targeting domain. We show that both mutants are fully functional as mitotic Cyclins when expressed in Xenopus oocytes, bind Cdc2 and activate M-phase promoting factor. fl 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.
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early development of mouse embryos null mutant for the Cyclin A2 gene occurs in the absence of maternally derived Cyclin A2 gene products
Developmental Biology, 2000Co-Authors: Nicola Winston, Christian Bréchot, Florence Bourgainguglielmetti, Maria A Ciemerych, Jacek Z Kubiak, Catherine Senamaudbeaufort, Mark Carrington, Joelle SobczakthepotAbstract:Progression through the mammalian cell cycle is regulated by the sequential activation and inactivation of the Cyclin-dependent kinases. In adult cells, Cyclin A2-dependent kinases are required for entry into S and M phases, completion of S phase, and centrosome duplication. However, mouse embryos lacking the Cyclin A2 gene nonetheless complete preimplantation development, but die soon after implantation. In this report, we investigated whether a contribution of maternal Cyclin A2 mRNA and protein to early embryonic cell cycles might explain these conflicting observations. Our data show that a maternal stock of Cyclin A2 mRNA is present in the oocyte and persists after fertilization until the second mitotic cell cycle, when it is degraded to undetectable levels coincident with transcriptional activation of the zygotic genome. A portion of maternally derived Cyclin A2 protein is stable during the first mitosis and persists in the cytoplasm, but is completely degraded at the second mitosis. The ability of Cyclin A2-null mutants to develop normally from the four-cell to the postimplantation stage in the absence of detectable Cyclin A2 gene product indicates therefore that Cyclin A2 is dispensable for cellular progression during the preimplantation nongrowth period of mouse embryo development.
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camp dependent positive control of Cyclin A2 expression during g1 s transition in primary hepatocytes
Biochemical and Biophysical Research Communications, 1999Co-Authors: Chantal Desdouets, Christian Bréchot, Catherine Senamaudbeaufort, G H Thoresen, Thoralf Christoffersen, Joelle SobczakthepotAbstract:cAMP positively and negatively regulates hepatocyte proliferation but its molecular targets are still unknown. Cyclin A2 is a major regulator of the cell cycle progression and its synthesis is required for progression to S phase. We have investigated whether Cyclin A2 and Cyclin A2-associated kinase might be one of the targets for the cAMP transduction pathway during progression of hepatocytes through G1 and G1/S. We show that stimulation of primary cultured hepatocytes by glucagon differentially modulated the expression of G1/S Cyclins. Glucagon indeed upregulated Cyclin A2 and Cyclin A2-associated kinase while Cyclin E-associated kinase was unmodified. In conclusion, our study identifies Cyclin A2 as an important effector of the cAMP transduction network during hepatocyte proliferation.
Debra J. Wolgemuth - One of the best experts on this subject based on the ideXlab platform.
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Distinct properties of Cyclin-dependent kinase complexes containing Cyclin A1 and Cyclin A2.
Biochemical and Biophysical Research Communications, 2008Co-Authors: Ayesha Joshi, Karen M. Lele, Vaidehi Jobanputra, Debra J. WolgemuthAbstract:The distinct expression patterns of the two A-type Cyclins during spermatogenesis and the absolute requirement for Cyclin A1 in this biological process in vivo suggest that they may confer distinct biochemical properties to their CDK partners. We therefore compared human Cyclin A1- and Cyclin A2-containing CDK complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate pRb and p53. Differences in biochemical activity were observed in CDK2 but not CDK1 when complexed with Cyclin A1 versus Cyclin A2. Further, CDK1/Cyclin A1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates pRb and p53 than CDK2/Cyclin A2. The activity of CDKs can therefore be regulated depending upon which A-type Cyclin they bind and CDK1/Cyclin A1 might be preferred in vivo.
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Cyclin A2 induces cardiac regeneration after myocardial infarction and prevents heart failure
Circulation Research, 2007Co-Authors: Richard Cheng, Debra J. Wolgemuth, Nurin H Dashoush, Haiying Tang, Tomohiro Asai, Rina J Kara, Kevin D Costa, Yoshifumi Naka, Hina W ChaudhryAbstract:Mammalian myocardial infarction is typically followed by scar formation with eventual ventricular dilation and heart failure. Here we present a novel model system in which mice constitutively expressing Cyclin A2 in the myocardium elicit a regenerative response after infarction and exhibit significantly limited ventricular dilation with sustained and remarkably enhanced cardiac function. New cardiomyocyte formation was noted in the infarcted zones as well as cell cycle reentry of periinfarct myocardium with an increase in DNA synthesis and mitotic indices. The enhanced cardiac function was serially assessed over time by MRI. Furthermore, the constitutive expression of Cyclin A2 appears to augment endogenous regenerative mechanisms via induction of side population cells with enhanced proliferative capacity. The ability of cultured transgenic cardiomyocytes to undergo cytokinesis provides mechanistic support for the regenerative capacity of Cyclin A2.
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Cyclin A2 mediates cardiomyocyte mitosis in the postmitotic myocardium
Journal of Biological Chemistry, 2004Co-Authors: Hina W Chaudhry, Nurin H Dashoush, Haiying Tang, Ling Zhang, Xiangyuan Wang, Debra J. WolgemuthAbstract:Cell cycle withdrawal limits proliferation of adult mammalian cardiomyocytes. Therefore, the concept of stimulating myocyte mitotic divisions has dramatic implications for cardiomyocyte regeneration and hence, cardiovascular disease. Previous reports describing manipulation of cell cycle proteins have not shown induction of cardiomyocyte mitosis after birth. We now report that Cyclin A2, normally silenced in the postnatal heart, induces cardiac enlargement because of cardiomyocyte hyperplasia when constitutively expressed from embryonic day 8 into adulthood. Cardiomyocyte hyperplasia during adulthood was coupled with an increase in cardiomyoctye mitosis, noted in transgenic hearts at all time points examined, particularly during postnatal development. Several stages of mitosis were observed within cardiomyocytes and correlated with the nuclear localization of Cyclin A2. Magnetic resonance analysis confirmed cardiac enlargement. These results reveal a previously unrecognized critical role for Cyclin A2 in mediating cardiomyocyte mitosis, a role that may significantly impact upon clinical treatment of damaged myocardium.
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the developmentally restricted pattern of expression in the male germ line of a murine Cyclin a Cyclin A2 suggests roles in both mitotic and meiotic cell cycles
Developmental Biology, 1996Co-Authors: Stuart E Ravnik, Debra J. WolgemuthAbstract:We have isolated cDNAs encoding a murine Cyclin A, designated CyclinA2, and have examined its in vivo expression at the level of both mRNA and protein, with particular focus on the male germ line. Cyclin A2 is expressed in embryos and in a variety of adult tissues, including the testis. In the testis, however, a striking cellular specificity of expression was observed. At both the DNA and protein levels, the predominant sites of Cyclin A2 expression were in the germ line stem cells, the spermatogonia, and in highest levels in preleptotene spermatocytes, cells in which premeiotic DNA synthesis occurs. The concurrent localization of Cyclin A2 mRNA and protein further suggested that Cyclin A2 is regulated at the level of transcription in these cells. The observed cellular specificity of Cyclin A2 expression is consistent with its function during mitosis in the stem cell stage of this lineage, while the restricted meiotic stage localization suggests function in G1/S or S but not in the meiotic divisions per se.
Benedicte Lemmers - One of the best experts on this subject based on the ideXlab platform.
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Cyclin A2 at the crossroads of cell cycle and cell invasion
World Journal of Biological Chemistry, 2015Co-Authors: Abdelhalim Loukil, Marion Peter, Nawal Bendris, Benedicte Lemmers, Caroline Cheung, Jean-marie BlanchardAbstract:Cyclin A2 is an essential regulator of the cell division cycle through the activation of kinases that participate to the regulation of S phase as well as the mitotic entry. However, whereas its degradation by the proteasome in mid mitosis was thought to be essential for mitosis to proceed, recent observations show that a small fraction of Cyclin A2 persists beyond metaphase and is degraded by autophagy. Its implication in the control of cytoskeletal dynamics and cell movement has unveiled its role in the modulation of RhoA activity. Since this GTPase is involved in both cell rounding early in mitosis and later, in the formation of the cleavage furrow, this suggests that Cyclin A2 is a novel actor in cytokinesis. Taken together, these data point to this Cyclin as a potential mediator of cell-niche interactions whose dysregulation could be taken as a hallmark of metastasis.
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Cyclin A2 modulates emt via β catenin and phospholipase c pathways
Carcinogenesis, 2015Co-Authors: Caroline Cheung, Jean-marie Blanchard, Nawal Bendris, Conception Paul, Abdallah Hamieh, Youssef Anouar, Michael Hahne, Benedicte LemmersAbstract:We have previously demonstrated that Cyclin A2 is involved in cytoskeletal dynamics, epithelial-mesenchymal transition (EMT) and metastasis. This phenotype was potentiated by activated oncogenic H-Ras. However, the mechanisms governing EMT in these cells have not yet been elucidated. Here, we dissected the pathways that are responsible for EMT in cells deficient for Cyclin A2. In Cyclin A2-depleted normal murine mammary gland (NMuMG) cells expressing RasV12, we found that β-catenin was liberated from the cell membrane and cell-cell junctions and underwent nuclear translocation and activation. Components of the canonical wingless (WNT) pathway, including WNT8b, WNT10a, WNT10b, frizzled 1 and 2 and TCF4 were upregulated at the messenger RNA and protein levels following Cyclin A2 depletion. However, suppression of the WNT pathway using the acetyltransferase porcupine inhibitor C59 did not reverse EMT whereas a dominant negative form of TCF4 as well as inhibition of phospholipase C using U73122 were able to do so. This suggests that a WNT-independent mechanism of β-catenin activation via phospholipase C is involved in the EMT induced by Cyclin A2 depletion. Our findings will broaden our knowledge on how Cyclin A2 contributes to EMT and metastasis.
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Cyclin A2 a novel regulator of emt
Cellular and Molecular Life Sciences, 2014Co-Authors: Nawal Bendris, Jean-marie Blanchard, Benedicte Lemmers, Caroline Cheung, Hon S Leong, John D Lewis, Ann F ChambersAbstract:Our previous work showed that Cyclin A2 deficiency promotes cell invasion in fibroblasts. Given that the majority of cancers emerge from epithelia, we explored novel functions for Cyclin A2 by depleting it in normal mammary epithelial cells. This caused an epithelial to mesenchymal transition (EMT) associated with loss of cell-to-cell contacts, decreased E-Cadherin expression and increased invasive properties characterized by a reciprocal regulation of RhoA and RhoC activities, where RhoA-decreased activity drove cell invasiveness and E-Cadherin delocalization, and RhoC-increased activity only supported cell motility. Phenotypes induced by Cyclin A2 deficiency were exacerbated upon oncogenic activated-Ras expression, which led to an increased expression of EMT-related transcriptional factors. Moreover, Cyclin A2-depleted cells exhibited stem cell-like properties and increased invasion in an in vivo avian embryo model. Our work supports a model where Cyclin A2 downregulation facilitates cancer cell EMT and metastatic dissemination.
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Cyclin A2 a genuine cell cycle regulator
Biomolecular Concepts, 2012Co-Authors: Nawal Bendris, Abdelhalim Loukil, Marion Peter, Nikola Arsic, Benedicte Lemmers, Caroline Cheung, Cosette Rebouissou, Robert A Hipskind, Jean-marie BlanchardAbstract:Abstract Cyclin A2 belongs to the core cell cycle regulators and participates in the control of both S phase and mitosis. However, several observations suggest that it is also endowed with other functions, and our recent data shed light on its involvement in cytoskeleton dynamic and cell motility. From the transcription of its gene to its posttranslational modifications, Cyclin A2 regulation reveals the complexity of the regulatory network shaping cell cycle progression. We summarize our current knowledge on this cell cycle regulator and discuss recent findings raising the possibility that Cyclin A2 might play a much broader role in epithelial tissues homeostasis.
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Cyclin A2 rho gtpases and emt
Small GTPases, 2012Co-Authors: Nawal Bendris, Nikola Arsic, Benedicte Lemmers, Jean-marie BlanchardAbstract:Cell cycle regulators, such as Cyclins, are often upregulated in many proliferative disorders, and Cyclin A2 is generally considered as a marker of aggressive cancers. Our recent work, which revealed decreased expression of Cyclin A2 upon metastasis of colorectal cancer, suggests a more complicated situation. Consistent with this, we identified a role for Cyclin A2, via RhoA, in regulation of the actin cytoskeleton and the control of cell invasion. Cyclin A2 also regulates spindle orientation which, when misoriented, could disrupt cell polarity and favor cancer cell detachment from the tumor as part of a transforming process, such as epithelial to mesenchymal transition (EMT). During EMT, cells undergo morphological and molecular changes toward a mesenchymal phenotype. Upregulation, or increased activity of some Rho GTPases, such as Cdc42, Rac1 or RhoC, increases the invasive potential of these cells. This correlates with the inverse relationship between RhoA and RhoC activities we observed in an epithelial cell type. Altogether, these observations raise the possibility that Cyclin A2 is instrumental in preventing EMT and therefore cancers of epithelial tissues.
