The Experts below are selected from a list of 106401 Experts worldwide ranked by ideXlab platform
Jenny L. Persson - One of the best experts on this subject based on the ideXlab platform.
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Cyclin A1 modulates the expression of vascular endothelial growth factor and promotes hormone-dependent growth and angiogenesis of breast cancer.
PloS one, 2013Co-Authors: Azharuddin Sajid Syed Khaja, Nishtman Dizeyi, Pirkko Härkönen, Lola Anagnostaki, Pradeep Kumar Kopparapu, Jenny L. PerssonAbstract:Alterations in cellular pathways related to both endocrine and vascular endothelial growth factors (VEGF) may contribute to breast cancer progression. Inhibition of the elevated levels of these pathways is associated with clinical benefits. However, molecular mechanisms by which endocrine-related pathways and VEGF signalling cooperatively promote breast cancer progression remain poorly understood. In the present study, we show that the A-type Cyclin, Cyclin A1, known for its important role in the initiation of leukemia and prostate cancer metastasis, is highly expressed in primary breast cancer specimens and metastatic lesions, in contrasting to its barely detectable expression in normal human breast tissues. There is a statistically significant correlation between Cyclin A1 and VEGF expression in breast cancer specimens from two patient cohorts (p
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Cyclin A1 modulates the expression of vascular endothelial growth factor and promotes hormone dependent growth and angiogenesis of breast cancer
PLOS ONE, 2013Co-Authors: Azharuddin Sajid Syed Khaja, Nishtman Dizeyi, Pirkko Härkönen, Lola Anagnostaki, Pradeep Kumar Kopparapu, Jenny L. PerssonAbstract:Alterations in cellular pathways related to both endocrine and vascular endothelial growth factors (VEGF) may contribute to breast cancer progression. Inhibition of the elevated levels of these pathways is associated with clinical benefits. However, molecular mechanisms by which endocrine-related pathways and VEGF signalling cooperatively promote breast cancer progression remain poorly understood. In the present study, we show that the A-type Cyclin, Cyclin A1, known for its important role in the initiation of leukemia and prostate cancer metastasis, is highly expressed in primary breast cancer specimens and metastatic lesions, in contrasting to its barely detectable expression in normal human breast tissues. There is a statistically significant correlation between Cyclin A1 and VEGF expression in breast cancer specimens from two patient cohorts (p<0.01). Induction of Cyclin A1 overexpression in breast cancer cell line MCF-7 results in an enhanced invasiveness and a concomitant increase in VEGF expression. In addition, there is a formation of protein-protein complexes between Cyclin A1 and estrogen receptor ER-α Cyclin A1 overexpression increases ER-α expression in MCF-7 and T47D cells. In mouse tumor xenograft models in which mice were implanted with MCF-7 cells that overexpressed Cyclin A1 or control vector, Cyclin A1 overexpression results in an increase in tumor growth and angiogenesis, which is coincident with an enhanced expression of VEGF, VEGFR1 and ER-α Our findings unravel a novel role for Cyclin A1 in growth and progression of breast cancer, and suggest that multiple cellular pathways, including cell cycle regulators, angiogenesis and estrogen receptor signalling, may cooperatively contribute to breast cancer progression.
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Characterization of the Novel Function of Cyclin A1 to Influence the Stem Cell Niche and Microenvironment Signaling in Mouse Model
Blood, 2011Co-Authors: Regina Miftakhova, Debra J. Wolgemuth, Andreas Hedblom, Anders Bredberg, Jenny L. PerssonAbstract:Abstract 2338 The molecules and cellular mechanisms that regulate pool size of hematopoietic stem cells and its association with stem cell niches to protect HSC from cell cycle-dependent injury are unclear. The cell cycle regulatory factor, Cyclin A1 is overexpressed in patients with hematopoietic malignancies. Further, targeted overexpression of Cyclin A1 in myeloid progenitor cells initiated acute myeloid leukemia in transgenic mice. In the present study, we investigated the role of Cyclin A1 in controlling the HSC pool and its functional association with key molecules that regulate stem cell niches under steady-state conditions or following the cytokine stimulation or radiation exposure in vivo and in vitro . We reported that Cyclin A1 null bone marrow displayed a significant increase in the frequency of stem cells (P
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characterization of the novel function of Cyclin A1 to influence the stem cell niche and microenvironment signaling in mouse model
Blood, 2011Co-Authors: Regina Miftakhova, Debra J. Wolgemuth, Andreas Hedblom, Anders Bredberg, Jenny L. PerssonAbstract:Abstract 2338 The molecules and cellular mechanisms that regulate pool size of hematopoietic stem cells and its association with stem cell niches to protect HSC from cell cycle-dependent injury are unclear. The cell cycle regulatory factor, Cyclin A1 is overexpressed in patients with hematopoietic malignancies. Further, targeted overexpression of Cyclin A1 in myeloid progenitor cells initiated acute myeloid leukemia in transgenic mice. In the present study, we investigated the role of Cyclin A1 in controlling the HSC pool and its functional association with key molecules that regulate stem cell niches under steady-state conditions or following the cytokine stimulation or radiation exposure in vivo and in vitro . We reported that Cyclin A1 null bone marrow displayed a significant increase in the frequency of stem cells (P<0,01) and increased expression of P27kip and increased phosphorylation of Akt at ser-473 site in HSCs and hematopoietic progenitors. We further showed that increased frequency and number of Cyclin A1 null HSCs was associated with the increased expression BMP receptor type IA that is known as a key molecule controlling the HSC niche. In addition, Cyclin A1 null HSCs exhibited increased ability to migrate as determined by in vitro migration assay , and bone marrow transplantation assay, and this correlated with the increased expression of MMP9, that is known for controlling the osteoblast cell expansion, and the accumulated nuclear localization of angiogenic and vascularization factor VEGFR2 in Cyclin A1 null bone marrow cells. We also observed that IRSp53 that is a regulator for extracellular matrix signaling, was present in the nuclear compartments of Cyclin A1 null bone marrow progenitor cells, but was absent in that of the wild-type controls. Further, flow cytometry and immunoblot analyses showed that Cyclin A1 null HSCs and progenitor cells exhibited relatively resistant to TNF stimulation and the radiation exposure, and this was associated with the great increase in the expression of phosporylated of ser-473 Akt. Our findings suggest that the microenvironment may be altered in bone marrows from Cyclin A1 null mice. Thus Cyclin A1 may have important function in the decision of maintaining the HSC pools and protecting the HSCs and progenitors from exposure to the external agents by regulating the interaction between the HSCs/progenitor cells and bone marrow environment. Disclosures: No relevant conflicts of interest to declare.
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Post-translational modification of Cyclin A1 is associated with staurosporine and TNFα induced apoptosis in leukemic cells
Molecular and Cellular Biochemistry, 2008Co-Authors: Jenny Ekberg, Jenny L. PerssonAbstract:Understanding of molecular mechanisms underlying the effects of cell cycle proteins in response to the chemotherapeutic agents is of great importance for improving the efficacy of targeted therapeutics and overcoming resistance to chemotherapeutic agents. Staurosporine and tumor necrosis factor alpha (TNFα) are the therapeutic agents that inhibit tumor cell growth by inducing cell death. Staurosporine induces apoptosis through the intrinsic pathway, while TNFα trigger the cell death via the extrinsic apoptotic pathway. We have previously demonstrated that the cell cycle regulatory protein, Cyclin A1 played an important role in the development of acute myeloid leukemia (AML), and Cyclin A1 expression correlated with disease characteristics and patient outcome in leukemia. However, it remains unknown how Cyclin A1 expression is regulated in leukemic cells treated with the therapeutic agents. Here, we demonstrate that Cyclin A1 protein is regulated by proteasome-mediated ubiquitination and degradation in untreated U-937 cells. Interestingly, ubiquitination- and proteasomal-mediated degradation of Cyclin A1 is prevented in cells treated with staurosporine or TNFα. Induction of apoptosis in U-937 cells by staurosporine or TNFα resulted in an increase in Cyclin A1 protein expression, which correlated well with Cyclin A1 protein modification and the activation of caspase-3. Blocking caspases activity by Z-VAD-FMK had no effect on the increased Cyclin A1 expression, suggesting that Cyclin A1 might be regulated by caspase-3 independent pathways. We further propose that CDC25C may be associated with Cyclin A1 protein modification in response to staurosporine or TNFα treatment. Our results suggest that Cyclin A1 protein is stabilized via post-transcriptional modification in response to apoptosis induced by staurosporine or TNFα.
Wolfgang E. Berdel - One of the best experts on this subject based on the ideXlab platform.
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A Limited Role for the Cell Cycle Regulator Cyclin A1 in Murine Leukemogenesis.
PloS one, 2015Co-Authors: Nicole Bäumer, Wolfgang E. Berdel, Sebastian Bäumer, Miriam Haak, Steffen Koschmieder, Kai Schönig, Carsten Müller-tidowAbstract:The quest for novel therapeutic targets in acute myeloid leukemia (AML) is still ongoing. One of such targets, Cyclin A1, was shown to be overexpressed in AML including AML stem cells. However, the function of Cyclin A1 in AML is largely unknown, and the data on its impact on patients´ survival remain controversial. Therefore, we developed a transgenic mouse model of stem cell-directed inducible Cyclin A1 overexpression and crossed these mice with PML-RARα-knockin mice, which develop an AML M3-like phenotype. To observe the effects of Cyclin A1 loss-of-function, we also crossed PML-RARα-knockin mice to Cyclin A1-knockout mice. Neither overexpression nor loss of Cyclin A1 significantly altered leukemogenesis in PML-RARα-knockin mice. These findings imply that upregulation of Cyclin A1 is not essential for leukemogenesis. Our data suggest that Cyclin A1 does not represent a suitable target for AML therapy.
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Cyclin A1 regulates WT1 expression in acute myeloid leukemia cells.
International journal of oncology, 2009Co-Authors: Utz Krug, Amber Yasmeen, Carmela Beger, Nicole Bäumer, Martin Dugas, Wolfgang E. Berdel, Carsten Müller-tidowAbstract:Cyclin A1 is a cell cycle protein that is expressed in testes, brain and CD34-positive hematopoietic progenitor cells. Cyclin A1 is overexpressed in a variety of myeloid leukemic cell lines and in myeloid leukemic blasts. Transgenic Cyclin A1 overexpressing mice develop acute myeloid leukemia with low frequency. In this study, we looked for putative target genes of Cyclin A1 in hematopoietic cells. Microarray analysis of U937 myeloid cells overexpressing Cyclin A1 versus conrol cells detected 35 differential expressed genes, 21 induced and 14 repressed ones upon Cyclin A1 overexpression. Among the differentially expressed genes WT1 was chosen for further analysis. Repression of WT1 expression was confirmed on the mRNA and protein level. In addition, WT1 expression was higher in bone marrow, liver and ovary of Cyclin A1-/- mice. Isoform analysis showed a profound change of the WT1 isoform ratio in U937 Cyclin A1-overexpressing versus control cells. Functional analysis revealed an inhibition of colony growth when WT1 isoforms were transfected into U937 cells, which was not affected by the overexpression of Cyclin A1. In addition, overexpression of the WT1-/+ isoform induced a G1 cell cycle arrest which was abrogated upon cotransfection with Cyclin A1. This study identified WT1 as a repressed target of Cyclin A1 and suggests that the suppression of WT1 in Cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells.
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DNA damage response involves modulation of Ku70 and Rb functions by Cyclin A1 in leukemia cells.
International journal of cancer, 2007Co-Authors: Nicole Bäumer, Sven Diederichs, Carmela Beger, Wolfgang E. Berdel, Taijun Yin, Feng Zhang, Karl Welte, Simone Fulda, Hubert ServeAbstract:Cyclin A1 plays a critical role in hematopoietic malignancies, notably, acute myeloid leukemia. The molecular mechanisms of Cyclin A1 action are incompletely understood. Here, we show that Cyclin A1 functions are mediated by the retinoblastoma and the Ku70 pathway. High levels of Cyclin A1 and the associated CDK2 kinase activity were associated with increasing levels of phosphorylated retinoblastoma in vivo. UV irradiation induced a switch of the CDK2 towards Cyclin A1, with accordance to changes in CDK2 kinase activity. The C-terminus of Cyclin A1 directly interacted with Ku70, and DNA binding activity of Ku70 was modulated by Cyclin A1/ CDK2 and phosphatase treatment. Cyclin A1-deficiency induced by shRNA increased apoptosis that is induced by DNA damage and death receptor ligands. Taken together, these analyses demonstrate that Cyclin A1 exerts antiapoptotic functions by interacting with retinoblastoma and Ku proteins in leukemia cells. ' 2007 Wiley-Liss, Inc.
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Analysis of the genetic interactions between Cyclin A1, Atm and p53 during spermatogenesis
Asian journal of andrology, 2007Co-Authors: Nicole Bäumer, Sven Diederichs, Gabriele Köhler, Carol Readhead, Jörg Gromoll, Feng Zhang, Marie Luise Sandstede, Etmar Bulk, Wolfgang E. BerdelAbstract:Aim To analyze the functional interactions of Cyclin with p53 and Atm in spermatogenesis and DNA double-strand break repair. Methods Two lines of double knockout mice were generated. Spermatogenesis and double strand break repair mechanisms were analyzed in Cyclin A1 (CcnA1); p53- and CcnA1; Atm-double knockout mice. Results The block in spermatogenesis observed in Cyclin A1-/- (CcnA1-/-) testes at the mid-diplotene stage is associated with polynucleated giant cells. We found that CcnA1-deficient testes and especially the giant cells accumulate unrepaired DNA double-strand breaks, as detected by immunohistochemistry for phosphorylated H2AX. In addition, the giant cells escape from apoptosis. The development of giant cells occurred in meiotic prophase I, because testes lacking ATM, which are known to develop spermatogenic arrest earlier than prophase I, do not develop giant cells in the absence of Cyclin A1. Cyclin A1 interacted with p53 and phosphorylated p53 in complex with CDK2. Interestingly, p53-deficiency significantly increased the number of giant cells in CcnA1-deficient testes. Gene expression analyses of a panel of DNA repair genes in the mutant testes revealed that none of the genes examined were consistently misregulated in the absence of Cyclin A1. Conclusion CcnA1-deficiency in spermatogenesis is associated with defects in DNA double-strand break repair, which is enhanced by loss of p53.
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Cyclin A1 the alternative a type Cyclin contributes to g1 s cell cycle progression in somatic cells
Oncogene, 2005Co-Authors: Shuchi Agrawal, Sven Diederichs, Carmela Beger, Nicole Bäumer, Wolfgang E. Berdel, Thomas Cauvet, Karl Welte, Annette Becker, Sascha Kowski, Hubert ServeAbstract:Cyclin A1 is an alternative A-type Cyclin that is essential for spermatogenesis, but it is also expressed in hematopoietic progenitor cells and in acute myeloid leukemia. Its functions during cell cycle progression of somatic cells are incompletely understood. Here, we have analysed the cell cycle functions of Cyclin A1 in transformed and nontransformed cells. Murine embryonic fibroblasts derived from Cyclin A1-deficient mice were significantly impaired in their proliferative capacity. In accordance, Cyclin A1-/- cells accumulated in G1 and G2/M phase while the percentage of S phase cells decreased. Also, lectin stimulated splenic lymphocytes from Cyclin A1-/- mice proliferated slower than their wild-type counterparts. Forced Cyclin A1 overexpression in NIH3T3 cells and in U937 leukemic cells either by transient transfection or by retroviral infection enhanced S phase entry. Consequently, siRNA mediated silencing of Cyclin A1 in highly Cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation. Taken together, these analyses demonstrate that Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, Cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth.
Debra J. Wolgemuth - One of the best experts on this subject based on the ideXlab platform.
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sp1 transcription factor and gatA1 cis acting elements modulate testis specific expression of mouse Cyclin A1
PLOS ONE, 2012Co-Authors: Sunil K Panigrahi, Ana Vasileva, Debra J. WolgemuthAbstract:Cyclin A1 is a male germ cell-specific cell cycle regulator that is essential for spermatogenesis. It is unique among the Cyclins by virtue of its highly restricted expression in vivo, being present in pachytene and diplotene spermatocytes and not in earlier or later stages of spermatogenesis. To begin to understand the molecular mechanisms responsible for this narrow window of expression of the mouse Cyclin A1 (CcnA1) gene, we carried out a detailed analysis of its promoter. We defined a 170-bp region within the promoter and showed that it is involved in repression of CcnA1 in cultured cells. Within this region we identified known cis-acting transcription factor binding sequences, including an Sp1-binding site and two GATA1-binding sites. Neither Sp1 nor GATA1 is expressed in pachytene spermatocytes and later stages of germ cell differentiation. Sp1 is readily detected at earlier stages of spermatogenesis. Site-directed mutagenesis demonstrated that neither factor alone was sufficient to significantly repress expression driven by the CcnA1 promoter, while concurrent binding of Sp1, and most likely GATA1 and possibly additional factors was inhibitory. Occupancy of Sp1 on the CcnA1 promoter and influence of GATA1-dependent cis-acting elements was confirmed by ChIP analysis in cell lines and most importantly, in spermatogonia. In contrast with many other testis-specific genes, the CpG island methylation status of the CcnA1 promoter was similar among various tissues examined, irrespective of whether CcnA1 was transcriptionally active, suggesting that this regulatory mechanism is not involved in the restricted expression of CcnA1.
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characterization of the novel function of Cyclin A1 to influence the stem cell niche and microenvironment signaling in mouse model
Blood, 2011Co-Authors: Regina Miftakhova, Debra J. Wolgemuth, Andreas Hedblom, Anders Bredberg, Jenny L. PerssonAbstract:Abstract 2338 The molecules and cellular mechanisms that regulate pool size of hematopoietic stem cells and its association with stem cell niches to protect HSC from cell cycle-dependent injury are unclear. The cell cycle regulatory factor, Cyclin A1 is overexpressed in patients with hematopoietic malignancies. Further, targeted overexpression of Cyclin A1 in myeloid progenitor cells initiated acute myeloid leukemia in transgenic mice. In the present study, we investigated the role of Cyclin A1 in controlling the HSC pool and its functional association with key molecules that regulate stem cell niches under steady-state conditions or following the cytokine stimulation or radiation exposure in vivo and in vitro . We reported that Cyclin A1 null bone marrow displayed a significant increase in the frequency of stem cells (P<0,01) and increased expression of P27kip and increased phosphorylation of Akt at ser-473 site in HSCs and hematopoietic progenitors. We further showed that increased frequency and number of Cyclin A1 null HSCs was associated with the increased expression BMP receptor type IA that is known as a key molecule controlling the HSC niche. In addition, Cyclin A1 null HSCs exhibited increased ability to migrate as determined by in vitro migration assay , and bone marrow transplantation assay, and this correlated with the increased expression of MMP9, that is known for controlling the osteoblast cell expansion, and the accumulated nuclear localization of angiogenic and vascularization factor VEGFR2 in Cyclin A1 null bone marrow cells. We also observed that IRSp53 that is a regulator for extracellular matrix signaling, was present in the nuclear compartments of Cyclin A1 null bone marrow progenitor cells, but was absent in that of the wild-type controls. Further, flow cytometry and immunoblot analyses showed that Cyclin A1 null HSCs and progenitor cells exhibited relatively resistant to TNF stimulation and the radiation exposure, and this was associated with the great increase in the expression of phosporylated of ser-473 Akt. Our findings suggest that the microenvironment may be altered in bone marrows from Cyclin A1 null mice. Thus Cyclin A1 may have important function in the decision of maintaining the HSC pools and protecting the HSCs and progenitors from exposure to the external agents by regulating the interaction between the HSCs/progenitor cells and bone marrow environment. Disclosures: No relevant conflicts of interest to declare.
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Characterization of the Novel Function of Cyclin A1 to Influence the Stem Cell Niche and Microenvironment Signaling in Mouse Model
Blood, 2011Co-Authors: Regina Miftakhova, Debra J. Wolgemuth, Andreas Hedblom, Anders Bredberg, Jenny L. PerssonAbstract:Abstract 2338 The molecules and cellular mechanisms that regulate pool size of hematopoietic stem cells and its association with stem cell niches to protect HSC from cell cycle-dependent injury are unclear. The cell cycle regulatory factor, Cyclin A1 is overexpressed in patients with hematopoietic malignancies. Further, targeted overexpression of Cyclin A1 in myeloid progenitor cells initiated acute myeloid leukemia in transgenic mice. In the present study, we investigated the role of Cyclin A1 in controlling the HSC pool and its functional association with key molecules that regulate stem cell niches under steady-state conditions or following the cytokine stimulation or radiation exposure in vivo and in vitro . We reported that Cyclin A1 null bone marrow displayed a significant increase in the frequency of stem cells (P
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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 A1-deficient mice lack histone H3 serine 10 phosphorylation and exhibit altered aurora B dynamics in late prophase of male meiosis.
Developmental biology, 2007Co-Authors: Helen D. Nickerson, Ayesha Joshi, Debra J. WolgemuthAbstract:Male mice lacking Cyclin A1 protein are sterile. Their sterility results from an arrest in the meiotic cell cycle of spermatocytes, which we now identify as occurring at late diplotene, immediately before diakinesis. The stage of arrest in Cyclin A1-deficient mice is distinct from the arrest seen in spermatocytes that are deficient in its putative catalytic partner Cdk2, which occurs much earlier in pachytene. The arrest in Cyclin A1-deficient spermatocytes is also accompanied by an unusual clustering of centromeric heterochromatin. Consistent with a possible defect in the centromeric region, immunofluorescent staining of Cyclin A1 protein shows localization in the region of the centromere. Phosphorylation of histone H3 at serine 10 in pericentromeric heterochromatin, which normally occurs in late diplotene, is reduced in spermatocytes from heterozygous CcnA1(+/-) testes and completely absent in spermatocytes with no Cyclin A1 protein. Concomitantly, the levels of pericentromeric aurora B kinase, known to phosphorylate histone H3 during meiosis, are partially reduced in spermatocytes from testes of heterozygous mice and further reduced in homozygous null spermatocytes. These data suggest a critical and concentration-dependent function for Cyclin A1 in the pericentromeric region in late diplotene of meiosis, perhaps in assembly or function of the passenger protein complex.
Sven Diederichs - One of the best experts on this subject based on the ideXlab platform.
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DNA damage response involves modulation of Ku70 and Rb functions by Cyclin A1 in leukemia cells.
International journal of cancer, 2007Co-Authors: Nicole Bäumer, Sven Diederichs, Carmela Beger, Wolfgang E. Berdel, Taijun Yin, Feng Zhang, Karl Welte, Simone Fulda, Hubert ServeAbstract:Cyclin A1 plays a critical role in hematopoietic malignancies, notably, acute myeloid leukemia. The molecular mechanisms of Cyclin A1 action are incompletely understood. Here, we show that Cyclin A1 functions are mediated by the retinoblastoma and the Ku70 pathway. High levels of Cyclin A1 and the associated CDK2 kinase activity were associated with increasing levels of phosphorylated retinoblastoma in vivo. UV irradiation induced a switch of the CDK2 towards Cyclin A1, with accordance to changes in CDK2 kinase activity. The C-terminus of Cyclin A1 directly interacted with Ku70, and DNA binding activity of Ku70 was modulated by Cyclin A1/ CDK2 and phosphatase treatment. Cyclin A1-deficiency induced by shRNA increased apoptosis that is induced by DNA damage and death receptor ligands. Taken together, these analyses demonstrate that Cyclin A1 exerts antiapoptotic functions by interacting with retinoblastoma and Ku proteins in leukemia cells. ' 2007 Wiley-Liss, Inc.
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Analysis of the genetic interactions between Cyclin A1, Atm and p53 during spermatogenesis
Asian journal of andrology, 2007Co-Authors: Nicole Bäumer, Sven Diederichs, Gabriele Köhler, Carol Readhead, Jörg Gromoll, Feng Zhang, Marie Luise Sandstede, Etmar Bulk, Wolfgang E. BerdelAbstract:Aim To analyze the functional interactions of Cyclin with p53 and Atm in spermatogenesis and DNA double-strand break repair. Methods Two lines of double knockout mice were generated. Spermatogenesis and double strand break repair mechanisms were analyzed in Cyclin A1 (CcnA1); p53- and CcnA1; Atm-double knockout mice. Results The block in spermatogenesis observed in Cyclin A1-/- (CcnA1-/-) testes at the mid-diplotene stage is associated with polynucleated giant cells. We found that CcnA1-deficient testes and especially the giant cells accumulate unrepaired DNA double-strand breaks, as detected by immunohistochemistry for phosphorylated H2AX. In addition, the giant cells escape from apoptosis. The development of giant cells occurred in meiotic prophase I, because testes lacking ATM, which are known to develop spermatogenic arrest earlier than prophase I, do not develop giant cells in the absence of Cyclin A1. Cyclin A1 interacted with p53 and phosphorylated p53 in complex with CDK2. Interestingly, p53-deficiency significantly increased the number of giant cells in CcnA1-deficient testes. Gene expression analyses of a panel of DNA repair genes in the mutant testes revealed that none of the genes examined were consistently misregulated in the absence of Cyclin A1. Conclusion CcnA1-deficiency in spermatogenesis is associated with defects in DNA double-strand break repair, which is enhanced by loss of p53.
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Cyclin A1 the alternative a type Cyclin contributes to g1 s cell cycle progression in somatic cells
Oncogene, 2005Co-Authors: Shuchi Agrawal, Sven Diederichs, Carmela Beger, Nicole Bäumer, Wolfgang E. Berdel, Thomas Cauvet, Karl Welte, Annette Becker, Sascha Kowski, Hubert ServeAbstract:Cyclin A1 is an alternative A-type Cyclin that is essential for spermatogenesis, but it is also expressed in hematopoietic progenitor cells and in acute myeloid leukemia. Its functions during cell cycle progression of somatic cells are incompletely understood. Here, we have analysed the cell cycle functions of Cyclin A1 in transformed and nontransformed cells. Murine embryonic fibroblasts derived from Cyclin A1-deficient mice were significantly impaired in their proliferative capacity. In accordance, Cyclin A1-/- cells accumulated in G1 and G2/M phase while the percentage of S phase cells decreased. Also, lectin stimulated splenic lymphocytes from Cyclin A1-/- mice proliferated slower than their wild-type counterparts. Forced Cyclin A1 overexpression in NIH3T3 cells and in U937 leukemic cells either by transient transfection or by retroviral infection enhanced S phase entry. Consequently, siRNA mediated silencing of Cyclin A1 in highly Cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation. Taken together, these analyses demonstrate that Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, Cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth.
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Cyclin A1 the alternative a type Cyclin contributes to g1 s cell cycle progression in somatic cells
Oncogene, 2005Co-Authors: Ping Ji, Sven Diederichs, Carmela Beger, Nicole Bäumer, Thomas Cauvet, Karl Welte, Shuchi Agrawal, Annette Becker, Sascha Kowski, Wolfgang E. BerdelAbstract:Cyclin A1, the alternative A-type Cyclin, contributes to G1/S cell cycle progression in somatic cells
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Cyclin A1, the alternative A-type Cyclin, contributes to G1/S cell cycle progression in somatic cells.
Oncogene, 2004Co-Authors: Shuchi Agrawal, Sven Diederichs, Carmela Beger, Nicole Bäumer, Thomas Cauvet, Karl Welte, Annette Becker, Sascha Kowski, Wolfgang E. BerdelAbstract:Cyclin A1 is an alternative A-type Cyclin that is essential for spermatogenesis, but it is also expressed in hematopoietic progenitor cells and in acute myeloid leukemia. Its functions during cell cycle progression of somatic cells are incompletely understood. Here, we have analysed the cell cycle functions of Cyclin A1 in transformed and nontransformed cells. Murine embryonic fibroblasts derived from Cyclin A1-deficient mice were significantly impaired in their proliferative capacity. In accordance, Cyclin A1-/- cells accumulated in G1 and G2/M phase while the percentage of S phase cells decreased. Also, lectin stimulated splenic lymphocytes from Cyclin A1-/- mice proliferated slower than their wild-type counterparts. Forced Cyclin A1 overexpression in NIH3T3 cells and in U937 leukemic cells either by transient transfection or by retroviral infection enhanced S phase entry. Consequently, siRNA mediated silencing of Cyclin A1 in highly Cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation. Taken together, these analyses demonstrate that Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, Cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth.
Hubert Serve - One of the best experts on this subject based on the ideXlab platform.
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DNA damage response involves modulation of Ku70 and Rb functions by Cyclin A1 in leukemia cells.
International journal of cancer, 2007Co-Authors: Nicole Bäumer, Sven Diederichs, Carmela Beger, Wolfgang E. Berdel, Taijun Yin, Feng Zhang, Karl Welte, Simone Fulda, Hubert ServeAbstract:Cyclin A1 plays a critical role in hematopoietic malignancies, notably, acute myeloid leukemia. The molecular mechanisms of Cyclin A1 action are incompletely understood. Here, we show that Cyclin A1 functions are mediated by the retinoblastoma and the Ku70 pathway. High levels of Cyclin A1 and the associated CDK2 kinase activity were associated with increasing levels of phosphorylated retinoblastoma in vivo. UV irradiation induced a switch of the CDK2 towards Cyclin A1, with accordance to changes in CDK2 kinase activity. The C-terminus of Cyclin A1 directly interacted with Ku70, and DNA binding activity of Ku70 was modulated by Cyclin A1/ CDK2 and phosphatase treatment. Cyclin A1-deficiency induced by shRNA increased apoptosis that is induced by DNA damage and death receptor ligands. Taken together, these analyses demonstrate that Cyclin A1 exerts antiapoptotic functions by interacting with retinoblastoma and Ku proteins in leukemia cells. ' 2007 Wiley-Liss, Inc.
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Cyclin A1 the alternative a type Cyclin contributes to g1 s cell cycle progression in somatic cells
Oncogene, 2005Co-Authors: Shuchi Agrawal, Sven Diederichs, Carmela Beger, Nicole Bäumer, Wolfgang E. Berdel, Thomas Cauvet, Karl Welte, Annette Becker, Sascha Kowski, Hubert ServeAbstract:Cyclin A1 is an alternative A-type Cyclin that is essential for spermatogenesis, but it is also expressed in hematopoietic progenitor cells and in acute myeloid leukemia. Its functions during cell cycle progression of somatic cells are incompletely understood. Here, we have analysed the cell cycle functions of Cyclin A1 in transformed and nontransformed cells. Murine embryonic fibroblasts derived from Cyclin A1-deficient mice were significantly impaired in their proliferative capacity. In accordance, Cyclin A1-/- cells accumulated in G1 and G2/M phase while the percentage of S phase cells decreased. Also, lectin stimulated splenic lymphocytes from Cyclin A1-/- mice proliferated slower than their wild-type counterparts. Forced Cyclin A1 overexpression in NIH3T3 cells and in U937 leukemic cells either by transient transfection or by retroviral infection enhanced S phase entry. Consequently, siRNA mediated silencing of Cyclin A1 in highly Cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation. Taken together, these analyses demonstrate that Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, Cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth.
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Successive increases in human Cyclin A1 promoter activity during spermatogenesis in transgenic mice.
International journal of molecular medicine, 2003Co-Authors: Carsten Müller-tidow, Rong Yang, Gregory Idos, Sven Diederichs, Wolfgang E. Berdel, Thomas Cauvet, Carol Readhead, Arthur H. Cohen, Kamlesh Asotra, Hubert ServeAbstract:The human Cyclin A1 gene is highly expressed in pachytene spermatocytes and is essential for spermatogenesis. To analyze mechanisms of Cyclin A1 gene expression in vivo, we cloned a 1.3 kb fragment of the promoter upstream of the cDNA of enhanced green fluorescent protein (EGFP). Four lines of transgenic mice were generated that carried the transgene. Cyclin A1 promoter activity in the organs of the transgenic mice was analyzed using fluorescence microscopy and flow cytometry. Expression of EGFP was seen in male germ cells of all four murine lines. Spermatogonia at the basal membrane expressed low levels of EGFP, but bright green fluorescence was present in spermatocytes entering meiosis. Interestingly, a further sharp increase in EGFP expression was found in spermatocytes approximately at the stage of the first meiotic division. EGFP levels stayed high thereafter and EGFP was present in mature spermatozoa. A portion of c-kit expressing cells in the testis also expressed EGFP indicating Cyclin A1 promoter activity in a subpopulation of spermatogonia. These data suggest that Cyclin A1 is active not only in pachytene spermatocytes but also in earlier phases of spermatogenesis.
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Cyclin A1 is highly expressed in aggressive testicular germ cell tumors
Cancer letters, 2003Co-Authors: Carsten Müller-tidow, Sven Diederichs, Wolfgang E. Berdel, Mark Schrader, Ulf Vogt, Kurt Miller, Hubert ServeAbstract:Cyclin A1 is a tissue-specific A-type Cyclin that is essential for spermatogenesis. Overexpression of Cyclin A1 was found in acute myeloid leukemia and Cyclin A1 induced leukemia in a transgenic mouse model. We used quantitative real-time reverse transcription-polymerase chain reaction to analyze Cyclin A1 expression in solid tumors. Cyclin A1 expression was very low in breast cancer, non-small cell lung cancer and in cervical carcinoma. However, substantial expression of Cyclin A1 was found in testicular and ovarian cancer and in endometrial cancer. In testis specimens, Cyclin A1 expression was much higher in testicular tumors compared to Sertoli cell only syndrome that lacks spermatogenesis. Compared to normal spermatogenesis, testicular cancers expressed on average lower levels of Cyclin A1. Among the different histological subtypes of testicular tumors, embryonal cell carcinomas and immature teratomas expressed the highest levels of Cyclin A1. The Cyclin A1 levels in these tumors were similar to those seen in normal testis. Seminomas and yolk sac tumors expressed intermediate levels, whereas Cyclin A1 expression was very low in mature teratomas. These findings indicate that Cyclin A1 is expressed in selected solid tumors. Its known oncogenic function and the high expression levels in aggressive testicular tumors suggest a role for Cyclin A1 in germ cell tumorigenesis.
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Cyclin A1 and gametogenesis in fertile and infertile patients: a potential new molecular diagnostic marker
Human reproduction (Oxford England), 2002Co-Authors: Mark Schrader, Sven Diederichs, Carsten Müller-tidow, Hubert Serve, Stuart E. Ravnik, Markus Müller, Wolfgang Schulze, Kurt MillerAbstract:BACKGROUND: The study aim was to evaluate Cyclin A1 mRNA expression levels as a potential molecular diagnostic parameter in the work-up of testicular tissue from fertile versus infertile patients. METHODS: Cyclin A1 expression was quantified in 55 cryopreserved testicular tissue specimens by fluorescence real-time RT–PCR. A conventional histological work-up was performed concomitantly in all tissue specimens with additional semi-thin sectioning in all cases of non-obstructive azoospermia (n 12), maturation arrest (n 17) and Sertoli cell-only syndrome (SCOS; n 9). RESULTS: The mean ( SD) normalized Cyclin A1 expression (N CyclinA1) was 3.82 2.23 relative gene expression (RGE) in tissue specimens with normal spermatogenesis, and 0.625 0.221 RGE in those with maturation arrest at the level of early spermatids. Only minimal NCyclinA1 was detected in tissue specimens with spermatogonia only or maturation arrest at the level of primary spermatocytes (0.005 0.008). Cyclin A1 expression was absent in the majority of SCOS specimens (0.002 0.002). CONCLUSIONS: These investigations suggested that Cyclin A1 expression is altered in cases of spermatogenic disorders. Moreover, the level of Cyclin A1 mRNA expression correlates with gametogenic disorders and seems well suited for a moleculardiagnostic classification supplementing the histopathological evaluation of spermatogenic disorders.
