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Yi, Xie, and Li Bing. "The Transcription Express Characteristics of Several Genes in the Process of Bombyx mori Ovarian Carcinoma." Advanced Materials Research 796 (September 2013): 39–42. http://dx.doi.org/10.4028/www.scientific.net/amr.796.39.
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Bombyx mori cell line (BmN) comes fromBombyx moriovary cell subculture. In order to study the change of several genes transcription in the process ofBombyx moriovary cells primary culture and subculture, we usedBombyx moriovary organizations and BmN cell lines as research materials, used Real Time fluorescent quantitative RT-PCR to detect cyclin gene family (CyclinA, CyclinB, CyclinB3, CyclinE, CyclinL1), p53 and Telomerase genes transcription level in the ovary and BmN cell lines, and took Actin3 gene as reference to dispose the results. The results showed that in theBombyx moriBmN cell lines the expression of CyclinA, CyclinB, CyclinB3, CyclinE, CyclinL1 and Telomerase genes were higher than those in the ovary. The expression of CyclinB in the BmN was more then 3.8 which was 76 times higher than that in the ovary; The expression of p53 gene in the BmN cell was lower than that in the ovary; The expression of Telomerase gene in the BmN cell was higher than that in the ovary. The results accumulated a reliable data for further study on the the role of cyclin gene family, p53 gene, and Telomerase gene in the process ofBombyx moriovarian carcinoma.
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Buchkovich, K. J., and E. B. Ziff. "Nerve growth factor regulates the expression and activity of p33cdk2 and p34cdc2 kinases in PC12 pheochromocytoma cells." Molecular Biology of the Cell 5, no. 11 (November 1994): 1225–41. http://dx.doi.org/10.1091/mbc.5.11.1225.
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In the absence of serum, nerve growth factor (NGF) promotes the survival and differentiation of the PC12 pheochromocytoma cell line. In the presence of serum, NGF acts primarily as a differentiation factor and negative regulator of cell cycling. To investigate NGF control of cell cycling, we have analyzed the regulation of cyclin dependent kinases during PC12 cell differentiation. NGF treatment leads to a reduction in the steady-state protein levels of p33cdk2 and p34cdc2, two key regulators of cell cycle progression. The decrease in p33cdk2 and p34cdc2 coincides with a decrease in the enzymatic activity of cyclinA-p34cdc2, cyclinB-p34cdc2, cyclinE-p33cdk2, and cyclinA-p33cdk2 kinases. The decline in p33cdk2 and p34cdc2 kinase activity in response to NGF is accelerated in cells that over-express the p140trk NGF receptor, suggesting that the timing of the down- regulation is dependent on the level of p140trk and the strength of the NGF signal. The level of cyclin A, a regulatory subunit of p33cdk2 and p34cdc2, is relatively constant during PC12 differentiation. Nevertheless, the DNA binding activity of the cyclinA-associated transcription factor E2F/DP decreases. Thus, NGF down-regulates the activity of cyclin dependent kinases and cyclin-transcription factor complexes during PC12 differentiation.
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Ehrhardt, Harald, Catarina Castro Alves, Franziska Wachter, and Irmela Jeremias. "TRAIL Preferentially Affects Cell Cycle-Arrested Tumor Cells Including Stem- and Progenitor Cells From Patients with Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 1879. http://dx.doi.org/10.1182/blood.v120.21.1879.1879.
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Abstract Abstract 1879 Leukemic stem- and progenitor cells exhibit low cycling activity which might represent a major cause for their increased treatment resistance. TRAIL (TNF-related apoptosis inducing ligand) is a novel putative anticancer drug currently in phase I and II clinical testing. We recently showed that TRAIL is able to address stem- and progenitor cells from patients with acute lymphoblastic leukemia (ALL) in xenotransplantation assays (Alves et al., Blood 2012,119,4224). As stem- and progenitor cells are often non-cycling, we asked here, whether TRAIL is able to address resting leukemia cells. We used cell lines and primary tumor cells from children with ALL which were amplified in severely immuno-compromised mice (NSG mice). Cell cycle arrest was induced (i) by addition of conventional cytotoxic drugs which are known to act as cytostatic drugs such as doxorubicine; (ii) by biochemical inhibitors known to induce cell cycle arrest at different defined points of the cell cycle such as mimosine; (iii) by molecular approaches and knockdown of cyclinB arresting cell cycle in G2 or knockdown of cyclinE arresting cell cycle in G1. Unexpectedly, TRAIL-induced apoptosis was enhanced, whenever cell cycle was arrested. Cell cycle arrest sensitized towards TRAIL-induced apoptosis independently from the point or phase of cell cycle which was arrested (G0, G1 or G2) and independently from the agent used to arrest the cell cycle. Similarly, knockdown of cyclinB or cyclinE both clearly sensitized cell line cells towards TRAIL-induced apoptosis. Cytotoxic drugs and cell cycle inhibitors might arrest the cell cycle by activation of p53. Accordingly, when caffeine was added which inhibited p53 activity and drug-induced cell cycle arrest, sensitization towards TRAIL-induced apoptosis was blocked. We have recently established a novel method which enables performing knockdown experiments in tumor cells derived from ALL patients (Höfig et al., Cell Comm. Signal. 2012,10,8). Using this method and most important for clinical translation, we could show that knockdown of either cyclinB or cyclinE clearly sensitized patient-derived ALL cells towards TRAIL-induced apoptosis. Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts anti-tumor activity preferentially against tumor cells in cell cycle arrest and less against actively cycling tumor cells. This special feature of TRAIL might explain its anti-tumor activity against stem- and progenitor cells in patients with ALL. Thus, TRAIL might represent an interesting drug to treat disease stages with accumulation of stem- and progenitor cells and static tumor disease, e.g., during minimal residual disease. Disclosures: No relevant conflicts of interest to declare.
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Kannan, Sankaranarayanan, Wendy Fang, and Patrick Zweidler-McKay. "Multiple Mechanisms of Notch-Mediated B-ALL Growth Arrest Via HES1 and PLK1: KIF11, CyclinB and p53." Blood 116, no. 21 (November 19, 2010): 3137. http://dx.doi.org/10.1182/blood.v116.21.3137.3137.
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Abstract Abstract 3137 Notch signaling inhibits B-ALL growth and survival, while it promotes T-ALL, revealing contrasting cell-specific consequences of Notch signaling in ALL subtypes. We previously reported that HES1 (Hairy and Enhancer of split1) is a Notch pathway member which is sufficient to reproduce these effects in B-ALL. We have found distinct HES1 protein complexes in B-ALL versus T-ALL, with significantly higher molecular weight complexes found in B-ALL. Through characterization of these complexes, multiple novel HES1 interacting proteins have been identified which regulate HES1 function as well as provide growth inhibiting and pro-apoptotic effects. We previously reported the novel role of HES1:PARP1 complexes in inducing B-ALL apoptosis. This study reports Polo-like kinase1 (PLK1) and Kinesin Family member 11 (KIF11, also known as Eg5) as novel HES1 interacting proteins in B-ALL. PLK1 is highly expressed in B cell leukemias and drives multiple proliferative pathways including activation of KIF11, induction of cyclinB and degradation of p53. KIF11 is also highly expressed in B-ALL and promotes cell cycle progression through enhanced spindle formation, while cyclinB promotes accelerated mitosis. Through HES1 immunoprecipitation and MALDI-TOF peptide analysis, we identified KIF11 as a potential HES1 interacting protein. Low flow size exclusion chromatography revealed that HES1 and KIF11 co-migrate in high molecular weight complexes. Reciprocal immunoprecipitation (IP) with HES1 and KIF11 antibodies reveal a strong protein-protein interaction in B-ALL cells. PLK1 was also identified in these complexes, revealing a novel interaction of HES1, KIF11 and PLK1. Importantly, induction of Notch signaling via HES1 in B-ALL decreases both PLK1 and KIF11 levels, associated with G1 cell cycle arrest. Furthermore, HES1 expression decreased cyclinB protein levels, but not cyclin A/E, consistent with inhibition of PLK1. Finally, in the same model we observe increased p53 and p21WAF1 protein levels, also contributing to growth arrest. These data reveal that multiple mechanisms of Notch/HES1-mediated growth arrest may occur via PLK1 in B-ALL. The novel interaction of HES1 with PLK1 and KIF11 and resulting effects on KIF11, cyclinB and p53/p21 pathways may represent important mechanisms of Notch-mediated growth inhibition in B-ALL. Disclosures: No relevant conflicts of interest to declare.
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Lammer, C., S. Wagerer, R. Saffrich, D. Mertens, W. Ansorge, and I. Hoffmann. "The cdc25B phosphatase is essential for the G2/M phase transition in human cells." Journal of Cell Science 111, no. 16 (August 15, 1998): 2445–53. http://dx.doi.org/10.1242/jcs.111.16.2445.
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Cdc25 phosphatases play key roles in cell cycle progression by activating cyclin-dependent kinases. In human cells, cdc25 proteins are encoded by a multigene family, consisting of cdc25A, cdc25B and cdc25C. While cdc25A plays a crucial role at the G1/S phase transition, cdc25C is involved in the dephosphorylation and activation of the mitotic kinase, cdc2/cyclinB. In addition, cdc25C itself is regulated by cdc2/cyclinB which then creates a positive feedback loop that controls entry into mitosis. In this study we show that the activity of cdc25B appears during late S phase and peaks during G2 phase. Both in vitro and in vivo cdc25B is activated through phosphorylation during S-phase. Using a cell duplication, microinjection assay we show that ablation of cdc25B function by specific antibodies blocks cell cycle progression in Hs68 cells by inhibition of entry into mitosis. Cdc25B function neither plays a role in later stages of mitosis nor for the inititation of DNA replication. These results indicate that cdc25B is a mitotic regulator that might act as a ‘starter phosphatase’ to initiate the positive feedback loop at the entry into M phase.
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Chiroli, Elena, Roberta Fraschini, Alessia Beretta, Mariagrazia Tonelli, Giovanna Lucchini, and Simonetta Piatti. "Budding yeast PAK kinases regulate mitotic exit by two different mechanisms." Journal of Cell Biology 160, no. 6 (March 17, 2003): 857–74. http://dx.doi.org/10.1083/jcb.200209097.
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We report the characterization of the dominant-negative CLA4t allele of the budding yeast CLA4 gene, encoding a member of the p21-activated kinase (PAK) family of protein kinases, which, together with its homologue STE20, plays an essential role in promoting budding and cytokinesis. Overproduction of the Cla4t protein likely inhibits both endogenous Cla4 and Ste20 and causes a delay in the onset of anaphase that correlates with inactivation of Cdc20/anaphase-promoting complex (APC)–dependent proteolysis of both the cyclinB Clb2 and securin. Although the precise mechanism of APC inhibition by Cla4t remains to be elucidated, our results suggest that Cla4 and Ste20 may regulate the first wave of cyclinB proteolysis mediated by Cdc20/APC, which has been shown to be crucial for activation of the mitotic exit network (MEN). We show that the Cdk1-inhibitory kinase Swe1 is required for the Cla4t-dependent delay in cell cycle progression, suggesting that it might be required to prevent full Cdc20/APC and MEN activation. In addition, inhibition of PAK kinases by Cla4t prevents mitotic exit also by a Swe1-independent mechanism impinging directly on the MEN activator Tem1.
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Ji, J. Y. "Genetic interactions between Cdk1-CyclinB and the Separase complex in Drosophila." Development 132, no. 8 (April 15, 2005): 1875–84. http://dx.doi.org/10.1242/dev.01780.
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Margolis, Seth S., Jennifer A. Perry, Douglas H. Weitzel, Christopher D. Freel, Minoru Yoshida, Timothy A. Haystead, and Sally Kornbluth. "A Role for PP1 in the Cdc2/Cyclin B–mediated Positive Feedback Activation of Cdc25." Molecular Biology of the Cell 17, no. 4 (April 2006): 1779–89. http://dx.doi.org/10.1091/mbc.e05-08-0751.
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The Cdc25 phosphatase promotes entry into mitosis through the removal of inhibitory phosphorylations on the Cdc2 subunit of the Cdc2/CyclinB complex. During interphase, or after DNA damage, Cdc25 is suppressed by phosphorylation at Ser287 (Xenopus numbering; Ser216 of human Cdc25C) and subsequent binding of the small acidic protein, 14-3-3. As reported recently, at the time of mitotic entry, 14-3-3 protein is removed from Cdc25 and S287 is dephosphorylated by protein phosphatase 1 (PP1). After the initial activation of Cdc25 and consequent derepression of Cdc2/CyclinB, Cdc25 is further activated through a Cdc2-catalyzed positive feedback loop. Although the existence of such a loop has been appreciated for some time, the molecular mechanism for this activation has not been described. We report here that phosphorylation of S285 by Cdc2 greatly enhances recruitment of PP1 to Cdc25, thereby accelerating S287 dephosphorylation and mitotic entry. Moreover, we show that two other previously reported sites of Cdc2-catalyzed phosphorylation on Cdc25 are required for maximal biological activity of Cdc25, but they do not contribute to PP1 regulation and do not act solely through controlling S287 phosphorylation. Therefore, multiple mechanisms, including enhanced recruitment of PP1, are used to promote full activation of Cdc25 at the time of mitotic entry.
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Mora, Catia Celeste, María Florencia Perotti, Eduardo González-Grandío, Pamela Anahí Ribone, Pilar Cubas, and Raquel Lía Chan. "AtHB40 modulates primary root length and gravitropism involving CYCLINB and auxin transporters." Plant Science 324 (November 2022): 111421. http://dx.doi.org/10.1016/j.plantsci.2022.111421.
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Ren, Liping, Anna Feoktistova, W. Hayes McDonald, Greg Den Haese, Jennifer L. Morrell, and Kathleen L. Gould. "Analysis of the Role of Phosphorylation in Fission Yeast Cdc13p/CyclinB Function." Journal of Biological Chemistry 280, no. 15 (February 10, 2005): 14591–96. http://dx.doi.org/10.1074/jbc.m500560200.
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Kaufmann, B., B. Wang, M. Lu, N. Hüser, H. Friess, G. von Figura, and D. Hartmann. "BRG1 Promotes Hepatocarcinogenesis by Modulating CyclinB, D, E and Matrix Metalloproteinase 7." HPB 21 (2019): S669. http://dx.doi.org/10.1016/j.hpb.2019.10.465.
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Resnitzky, D., M. Gossen, H. Bujard, and S. I. Reed. "Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system." Molecular and Cellular Biology 14, no. 3 (March 1994): 1669–79. http://dx.doi.org/10.1128/mcb.14.3.1669-1679.1994.
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Conditional overexpression of human cyclins B1, D1, and E was accomplished by using a synthetic cDNA expression system based on the Escherichia coli tetracycline repressor. After induction of these cyclins in asynchronous Rat-1 fibroblasts, a decrease in the length of the G1 interval was observed for cyclins D1 and E, consistent with an acceleration of the G1/S phase transition. We observed, in addition, a compensatory lengthening of S phase and G2 so that the mean cell cycle length in populations constitutively expressing these cyclins was unchanged relative to those of their uninduced counterparts. We found that expression of cyclin B1 had no effect on cell cycle dynamics, despite elevated levels of cyclin B-associated histone H1 kinase activity. Induction of cyclins D1 and E also accelerated entry into S phase for synchronized cultures emerging from quiescence. However, whereas cyclin E exerted a greater effect than cyclin D1 in asynchronous cycling cells, cyclin D1 conferred a greater effect upon stimulation from quiescence, suggesting a specific role for cyclin D1 in the G0-to-G1 transition. Overexpression of cyclins did not prevent cells from entering into quiescence upon serum starvation, although a slight delay in attainment of quiescence was observed for cells expressing either cyclin D1 or cyclin E. These results suggest that cyclins D1 and E are rate-limiting activators of the G1-to-S phase transition and that cyclin D1 might play a specialized role in facilitating emergence from quiescence.
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Resnitzky, D., M. Gossen, H. Bujard, and S. I. Reed. "Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system." Molecular and Cellular Biology 14, no. 3 (March 1994): 1669–79. http://dx.doi.org/10.1128/mcb.14.3.1669.
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Conditional overexpression of human cyclins B1, D1, and E was accomplished by using a synthetic cDNA expression system based on the Escherichia coli tetracycline repressor. After induction of these cyclins in asynchronous Rat-1 fibroblasts, a decrease in the length of the G1 interval was observed for cyclins D1 and E, consistent with an acceleration of the G1/S phase transition. We observed, in addition, a compensatory lengthening of S phase and G2 so that the mean cell cycle length in populations constitutively expressing these cyclins was unchanged relative to those of their uninduced counterparts. We found that expression of cyclin B1 had no effect on cell cycle dynamics, despite elevated levels of cyclin B-associated histone H1 kinase activity. Induction of cyclins D1 and E also accelerated entry into S phase for synchronized cultures emerging from quiescence. However, whereas cyclin E exerted a greater effect than cyclin D1 in asynchronous cycling cells, cyclin D1 conferred a greater effect upon stimulation from quiescence, suggesting a specific role for cyclin D1 in the G0-to-G1 transition. Overexpression of cyclins did not prevent cells from entering into quiescence upon serum starvation, although a slight delay in attainment of quiescence was observed for cells expressing either cyclin D1 or cyclin E. These results suggest that cyclins D1 and E are rate-limiting activators of the G1-to-S phase transition and that cyclin D1 might play a specialized role in facilitating emergence from quiescence.
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Yang, Guang, Zhendong Qin, Zhijie Lu, Rishen Liang, Lijuan Zhao, Gan Pan, Li Lin, and Kai Zhang. "Comparative Transcriptomics of Gonads Reveals the Molecular Mechanisms Underlying Gonadal Development in Giant Freshwater Prawns (Macrobrachium rosenbergii)." Journal of Marine Science and Engineering 10, no. 6 (May 27, 2022): 737. http://dx.doi.org/10.3390/jmse10060737.
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The giant freshwater prawn, Macrobrachium rosenbergii, is a prawn that has economic significance throughout the world. It exhibits sex-related growth dimorphism, whereby the males grow significantly more rapidly than the females. Therefore, a study on the molecular regulatory mechanism, which underlies the sexual differentiation of M. rosenbergii, is of both scientific and commercial importance. However, a scarcity of genomic and transcriptomic resources severely limits our knowledge of the sexual differentiation mechanisms in M. rosenbergii. Here, transcriptome sequencing of several gonadic samples of males and females in M. rosenbergii was performed to investigate the molecular basis underlying gonadal development. Our results showed that 2149 unigenes presented as differentially expressed genes (DEGs) in the ovaries of females compared to the testes of males, which contained 484 down-regulated and 1665 up-regulated genes. Enrichment analysis of DEGs revealed many of these genes to be related to sexual differentiation and gonadal development. From our transcriptome analyses, and as confirmed by quantitative real-time PCR, male-related genes (Mrr, MRPINK, IR, IAGBP, TESK1, and dsx) in the testes were significantly up-regulated, and female-related genes (ERR, Sxl3, cyclinB, Dmrt99B, PPP2A, and ADCY9) in the ovaries were also significantly up-regulated. This indicates the potential role these genes play in the gonadal development of M. rosenbergii. Furthermore, multiple signal transduction pathways relating to gonadal maturation and spermatogenesis, including MAPK, were identified herein. Our data also supports previous ideas that IAG and IAGBP-IR signaling schemes could help in the regulation of testis’ development in M. rosenbergii and the ERR gene could regulate ovarian development by affecting the expression of cyclinB, PPP2A, and ADCY9. The data from this study provides incredibly usefully genomic resources for future research on the sexual differentiation and practical aquaculture of M. rosenbergii.
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Li, Pihong, Luguang Liu, Xiangguo Dang, and Xingsong Tian. "Romidepsin Induces G2/M Phase Arrest and Apoptosis in Cholangiocarcinoma Cells." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382096075. http://dx.doi.org/10.1177/1533033820960754.
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Background: Cholangiocarcinoma (CCA) is an extremely intractable malignancy since most patients are already in an advanced stage when firstly discovered. CCA needs more effective treatment, especially for advanced cases. Our study aimed to evaluate the effect of romidepsin on CCA cells in vitro and in vivo and explore the underlying mechanisms. Methods: The antitumor effect was determined by cell viability, cell cycle and apoptosis assays. A CCK-8 assay was performed to measure the cytotoxicity of romidepsin on CCA cells, and flow cytometry was used to evaluate the effects of romidepsin on the cell cycle and apoptosis. Moreover, the in vivo effects of romidepsin were measured in a CCA xenograft model. Results: Romidepsin could reduce the viability of CCA cells and induce G2/M cell cycle arrest and apoptosis, indicating that romidepsin has a significant antitumor effect on CCA cells in vitro. Mechanistically, the antitumor effect of romidepsin on the CCA cell lines was mediated by the induction of G2/M cell cycle arrest and promotion of cell apoptosis. The G2/M phase arrest of the CCA cells was associated with the downregulation of cyclinB and upregulation of the p-cdc2 protein, resulting in cell cycle arrest. The apoptosis of the CCA cells induced by romidepsin was attributed to the activation of caspase-3. Furthermore, romidepsin significantly inhibited the growth of the tumor volume of the CCLP-1 xenograft, indicating that romidepsin significantly inhibited the proliferation of CCA cells in vivo. Conclusions: Romidepsin suppressed the proliferation of CCA cells by inducing cell cycle arrest through cdc2/cyclinB and cell apoptosis by targeting caspase-3/PARP both in vitro and in vivo, indicating that romidepsin is a potential therapeutic agent for CCA.
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García-Blanco, Natalia, Alicia Vázquez-Bolado, and Sergio Moreno. "Greatwall-Endosulfine: A Molecular Switch that Regulates PP2A/B55 Protein Phosphatase Activity in Dividing and Quiescent Cells." International Journal of Molecular Sciences 20, no. 24 (December 10, 2019): 6228. http://dx.doi.org/10.3390/ijms20246228.
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During the cell cycle, hundreds of proteins become phosphorylated and dephosphorylated, indicating that protein kinases and protein phosphatases play a central role in its regulation. It has been widely recognized that oscillation in cyclin-dependent kinase (CDK) activity promotes DNA replication, during S-phase, and chromosome segregation, during mitosis. Each CDK substrate phosphorylation status is defined by the balance between CDKs and CDK-counteracting phosphatases. In fission yeast and animal cells, PP2A/B55 is the main protein phosphatase that counteracts CDK activity. PP2A/B55 plays a key role in mitotic entry and mitotic exit, and it is regulated by the Greatwall-Endosulfine (ENSA) molecular switch that inactivates PP2A/B55 at the onset of mitosis, allowing maximal CDK activity at metaphase. The Greatwall-ENSA-PP2A/B55 pathway is highly conserved from yeast to animal cells. In yeasts, Greatwall is negatively regulated by nutrients through TORC1 and S6 kinase, and couples cell growth, regulated by TORC1, to cell cycle progression, driven by CDK activity. In animal cells, Greatwall is phosphorylated and activated by Cdk1 at G2/M, generating a bistable molecular switch that results in full activation of Cdk1/CyclinB. Here we review the current knowledge of the Greatwall-ENSA-PP2A/B55 pathway and discuss its role in cell cycle progression and as an integrator of nutritional cues.
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Zhang, Wenqing, Daniele Bergamaschi, Boquan Jin, and Xin Lu. "Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivo." Blood 105, no. 9 (May 1, 2005): 3691–98. http://dx.doi.org/10.1182/blood-2003-07-2558.
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AbstractUsing 2-dimensional gel electrophoresis (2D-gel) analysis, we show here that cell-cycle entry is associated with a significant increase in p27kip1 phosphorylation in human primary B cells. A similar pattern of increase in p27kip1 phosphorylation was also seen in 2 fast-growing tumor cell lines, Burkitt lymphoma cell line BL40 and breast carcinoma cell line Cal51, where inactive p27kip1 is expressed at high levels. Detailed analysis revealed for the first time that different cyclins and cyclin-dependent kinases (cdk's) interact with distinct posttranslationally modified isoforms of p27kip1 in vivo. Cyclin E but not cyclin A selectively interacts with phosphorylated p27kip1 isoforms, while cyclin D1 and D2 favor unphosphorylated p27kip1 isoforms in vivo. Interestingly, cyclin D3 and cdk4 selectively interact with phosphorylated p27kip1 in BL40 cells. Among all D-type cyclin/cdk4 and cdk6 complexes, cyclin D3/cdk4 is most active in sequestering the inhibitory activity of p27kip1 in vitro in a cyclinE/cdk2 kinase assay. This novel feature of the binding specificity of p27kip1 to cyclins and cdk's in vivo is interpreted in the context of overexpression of cyclin D3 in the presence of high levels of p27kip1 in human B-cell lymphomas with adverse clinical outcome.
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Kannan, Sankaranarayanan, Mandy A. Hall, Leonard S. Golfman, and Patrick A. Zweidler-McKay. "Notch Signaling In B-ALL Reveals PLK1 As A Potential Therapeutic Target In B-ALL: PLK1-Selective Inhibitor Poloxin Modulates Cyclin B and P53 Pathways, Leading To Growth Arrest and Apoptosis." Blood 122, no. 21 (November 15, 2013): 2912. http://dx.doi.org/10.1182/blood.v122.21.2912.2912.
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Abstract Background Notch is a well-known oncogene in T-ALL, yet appears to have tumor suppressor effects in B-ALL. These cell type-specific effects of Notch signaling mirror consequences seen in early lymphocyte development and raises the question of how Notch leads to such divergent consequences in closely related cell types. In exploring these Notch mechanisms we discovered a B-ALL specific Notch-mediated reduction in the cell cycle regulator Polo-like kinase-1 (PLK1), revealing a novel targetable kinase in B-ALL. Approach To explore the consequences of Notch-mediated down regulation of cell cycle regulator kinase PLK1, we targeted PLK1 kinase function with the novel PLK1-selective inhibitor poloxin in human B-ALL lines. Results PLK1 is highly expressed in B-ALL verses normal tissues (panel A), correlates with cyclin B expression, is expressed >2-fold higher in B-ALL with t(1;19) than other B-ALL samples, and may predict response of ALL to methotrexate. In our panel of human B-ALL cell lines poloxin induced G2/M growth arrest and decreased cell number by >80% (panel B), and decreased survival in B-ALL cells (>75% AnnexinV+, panel C). PLK1 inhibition led to tumor suppressor p53 stabilization, revealing >5-fold increase in p53 protein levels following poloxin treatment in B-ALL (panel D). Mechanistically, PLK1 inhibition leads to both cytoplasmic re-localization of cyclin B, disrupting the CDC2-cyclinB complex, as well as phosphorylation of p53 at Ser20, which destabilizes p53-MDM2 interaction and thus accumulation of p53. Conclusions While exploring the mechanisms of cell type-specific effects of Notch signaling in ALL, we have found a novel therapeutic target, the cell cycle regulator PLK1. Our findings reveal a novel therapeutic approach whereby PLK1-selective inhibition via poloxin induces growth arrest and apoptosis in human B-ALL via consequences on cyclin B and p53 pathways. Disclosures: No relevant conflicts of interest to declare.
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Zhong, Ailing, Hui Zheng, Hongqin Zhang, Jiajun Sun, Jiabin Shen, Minjie Deng, Miaomiao Chen, Renquan Lu, and Lin Guo. "MUS81 Inhibition Increases the Sensitivity to Therapy Effect in Epithelial Ovarian Cancer via Regulating CyclinB Pathway." Journal of Cancer 10, no. 10 (2019): 2276–87. http://dx.doi.org/10.7150/jca.30818.
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Cogswell, J. P., M. M. Godlevski, M. Bonham, J. Bisi, and L. Babiss. "Upstream stimulatory factor regulates expression of the cell cycle-dependent cyclin B1 gene promoter." Molecular and Cellular Biology 15, no. 5 (May 1995): 2782–90. http://dx.doi.org/10.1128/mcb.15.5.2782.
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Progression through the somatic cell cycle requires the temporal regulation of cyclin gene expression and cyclin protein turnover. One of the best-characterized examples of this regulation is seen for the B-type cyclins. These cyclins and their catalytic component, cdc2, have been shown to mediate both the entry into and maintenance of mitosis. The cyclin B1 gene has been shown to be expressed between the late S and G2 phases of the cell cycle, while the protein is degraded specifically at interphase via ubiquitination. To understand the molecular basis for transcriptional regulation of the cyclin B1 gene, we cloned the human cyclin B1 gene promoter region. Using a chloramphenicol acetyltransferase reporter system and both stable and transient assays, we have shown that the cyclin B1 gene promoter (extending to -3800 bp relative to the cap site) can confer G2-enhanced promoter activity. Further analysis revealed that an upstream stimulatory factor (USF)-binding site and its cognate transcription factor(s) are critical for expression from the cyclin B1 promoter in cycling HeLa cells. Interestingly, USF DNA-binding activity appears to be regulated in a G2-specific fashion, supporting the idea that USF may play some role in cyclin B1 gene activation. These studies suggest an important link between USF and the cyclin B1 gene, which in part explains how maturation promoting factor complex formation is regulated.
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Traganos, Frank. "Cycling without Cyclins." Cell Cycle 3, no. 1 (January 2004): 31–33. http://dx.doi.org/10.4161/cc.3.1.608.
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Holding, Cathy. "Cycling without cyclins." Genome Biology 5 (2004): spotlight—20040824–01. http://dx.doi.org/10.1186/gb-spotlight-20040824-01.
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Zhang, Demei, Rui Wang, Shijian Han, Zhigang Li, Jiming Xiao, Yangrui Li, Lingqiang Wang, and Suli Li. "Transcriptome Analysis of between Sugarcane Young Leaves and Protoplasts after Enzymatic Digestion." Life 12, no. 8 (August 9, 2022): 1210. http://dx.doi.org/10.3390/life12081210.
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Sugarcane somatic cell hybridization can break through the barrier of genetic incompatibility between distantly related species in traditional breeding. However, the molecular mechanisms of sugarcane protoplast regeneration and the conditions for protoplast preparation remain largely unknown. In this study, young sugarcane (ROC22) leaves were enzymatically digested, and the viability of protoplasts reached more than 90% after enzymatic digestion (Enzymatic combination: 2% cellulase + 0.5% pectinase + 0.1% dissociative enzyme + 0.3% hemicellulase, pH = 5.8). Transcriptome sequencing was performed on young sugarcane leaves and protoplasts after enzymatic digestion to analyze the differences in gene expression in somatic cells before and after enzymatic digestion. A total of 117,411 unigenes and 43,460 differentially expressed genes were obtained, of which 21,123 were up-regulated and 22,337 down-regulated. The GO terms for the 43,460 differentially expressed genes (DEGs) were classified into three main categories: biological process, cellular component and molecular function, which related to developmental process, growth, cell proliferation, transcription regulator activity, signal transducer activity, antioxidant activity, oxidative stress, kinase activity, cell cycle, cell differentiation, plant hormone signal transduction, and so on. After enzymatic digestion of young sugarcane leaves, the expressions of GAUT, CESA, PSK, CyclinB, CyclinA, CyclinD3 and cdc2 genes associated with plant regeneration were significantly down-regulated to 65%, 47%, 2%, 18.60%, 21.32%, 52% and 45% of young leaves, respectively. After enzymatic digestion, Aux/IAA expression was up-regulated compared with young leaves, and Aux/IAA expression was 3.53 times higher than that of young leaves. Compared with young leaves, these key genes were significantly changed after enzymatic digestion. These results indicate that the process of somatic enzymatic digestion process may affect the regeneration of heterozygous cells to a certain extent.
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Hyer, Marc L., Jimmy Fourtounis, David Gallo, Vivek Bhaskaran, Rino Stocco, Rosie Kryczka, Sai Save, et al. "Abstract C163: KRAS alterations combined with TP53 mutations as novel synthetic lethal genomic lesions for PKMYT1 inhibition." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): C163. http://dx.doi.org/10.1158/1535-7163.targ-23-c163.
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Abstract Background: Membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) is a cell cycle regulatory kinase that inhibits CDK1/CyclinB activity, delaying entry into mitosis in tumor cells experiencing replication stress (RS). RS is frequently induced by genetic alterations that drive premature transition from G1 to S phase, promoting genome instability and creating a synthetic lethal (SL) relationship between these specific alterations and PKMYT1 inhibition. This relationship has been demonstrated preclinically and clinically with CCNE1 amplification and FBXW7 mutations, common alterations in ovarian and colorectal cancers, respectively. Oncogenic KRAS gain of function (GOF) mutations, combined with TP53 alterations, are bona fide drivers of RS. Here we investigate the relationship between KRAS/TP53 alterations and PKMYT1 inhibition, mediated by the first-in-class, potent and selective PKMYT1 inhibitor lunresertib (RP-6306), alone or in combination with RS-inducing agents. Methods: KRAS/TP53 double mutant isogenic cell pairs, across relevant tumor origins, were genetically engineered to express multiple KRAS GOF mutant codons and alleles (G12D, G12C, G12V, G12R, G13D and Q61H). Cell cycle distribution perturbations and RS were evaluated. Sensitivity to lunresertib alone or in combination with chemotherapeutic or targeted agents was assessed by cell growth assays. In vitro findings were further evaluated in KRAS/TP53 double mutant patient-derived xenografts (PDX). Results: Lunresertib inhibited the growth of isogenic KRAS/TP53 double mutant cells, with up to a 12-fold EC50 shift compared to control parental cells. Combination of lunresertib with RS-inducing chemotherapeutic agents (eg. gemcitabine), or the ATR inhibitor camonsertib (RP-3500) led to synergistic cell growth inhibition in KRAS/TP53 mutant cells at significantly lower concentrations than in wild type lines. Mechanistically, KRAS/TP53 isogenic cells showed elongated S-phase and increased cyclin B1 levels, phenocopying the effects of CCNE1 amplification. Lunresertib induced premature mitosis and DNA damage in KRAS/TP53 mutant cells, sparing parental cell lines. PDX efficacy studies demonstrated robust combination benefit in pancreatic, lung and colorectal settings, with durable tumor regressions and complete responses observed. Conclusion: GOF KRAS mutations, when combined with TP53 alterations, show a strong SL relationship with PKMYT1 inhibition, alone or in combination with RS-inducing antitumor agents. Importantly, the SL phenotype was observed across multiple tumor indications and KRAS mutant codons/alleles, suggesting a potential broad scope of clinical utility beyond approved KRAS inhibitors. The mechanism is similar to CCNE1 amplification, characterized by enhanced G1/S transition driving heightened dependence on PKMYT1 to inhibit CDK1/CyclinB. Taken together, our data form rationale for the therapeutic evaluation of PKMYT1 inhibitors in KRAS/TP53 altered tumors and uncover a potential new patient selection biomarker for lunresertib. Citation Format: Marc L. Hyer, Jimmy Fourtounis, David Gallo, Vivek Bhaskaran, Rino Stocco, Rosie Kryczka, Sai Save, Helen Burston, Olivier Nicolas, Stephen Morris, Anne Roulston, Jordan T. F. Young, Michal Zimmermann, C. Gary Marshall, Artur Veloso, Elia Aguado-Fraile. KRAS alterations combined with TP53 mutations as novel synthetic lethal genomic lesions for PKMYT1 inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C163.
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Wang, Jia-Hao, Yan Li, Shou-Long Deng, Yi-Xun Liu, Zheng-Xing Lian, and Kun Yu. "Recent Research Advances in Mitosis during Mammalian Gametogenesis." Cells 8, no. 6 (June 10, 2019): 567. http://dx.doi.org/10.3390/cells8060567.
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Mitosis is a highly sophisticated and well-regulated process during the development and differentiation of mammalian gametogenesis. The regulation of mitosis plays an essential role in keeping the formulation in oogenesis and gametogenesis. In the past few years, substantial research progress has been made by showing that cyclins/cyclin-dependent kinase (CDK) have roles in the regulation of meiosis. In addition, more functional signaling molecules have been discovered in mitosis. Growing evidence has also indicated that miRNAs influence cell cycling. In this review, we focus on specific genes, cyclins/Cdk, signaling pathways/molecules, and miRNAs to discuss the latest achievements in understanding their roles in mitosis during gametogenesis. Further elucidation of mitosis during gametogenesis may facilitate delineating all processes of mammalian reproduction and the development of disease treatments.
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Husdal, A., G. Bukholm, and I. R. K. Bukholm. "The Prognostic Value and Overexpression of Cyclin A Is Correlated with Gene Amplification of both Cyclin A and Cyclin E in Breast Cancer Patient." Analytical Cellular Pathology 28, no. 3 (January 1, 2006): 107–16. http://dx.doi.org/10.1155/2006/721919.
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Deregulation of cell cycle control is a hallmark of cancer. The primary cyclins (A, B1, D1, D3 and E) are crucial for cell cycle progression. Secondary cyclins (C and H) have putative indirect effects on cell cycle propulsion and are not previously evaluated in breast cancer. We have examined protein expression and gene amplification of cyclins in breast carcinomas and correlated the findings with clinical follow-up data. We have previously demonstrated that over-expression of cyclin A is associated with poor prognosis in breast cancer patients. In this study we wanted to evaluate the mechanisms behinde overexpression of cyclin A, as well as the impact of other cyclins, both at the gene level and at the protein level, on prognosis of breast cancer patients. The impact of TP53 gene mutations on gene amplification of cyclins was also evaluated. Methods: Real-Time Quantitative PCR was used to detect gene amplification of cyclins in tumour tissue from 86 patients operated for invasive breast carcinomas, while immunohistochemistry was applied to detect protein expression of the same cyclins. Result: Of the 80-breast tumour samples available for cyclin A gene amplification analyses, 26.7% (23/80) was defined to have cyclin A gene amplification. 37.2% (32/79) had cyclin B1 gene amplification, 82.6% (71/82) of the samples harboured amplification of cyclin C gene, 74.4% (64/82) had cyclin D1 gene amplification, 41.9% (36/86) had cyclin D3 gene amplification, 29.1% (25/81) of the patients had cyclin E gene amplification and 9.3% (8/86) of the samples showed amplification of the cyclin H gene. When correlation between gene amplification and protein expression was evaluated, we observed a statistical significant correlation between gene amplification and protein expression of cyclin A (p = 0.009) and cyclin D3 (p < 0.001). However, the correlation between gene amplification and protein expression of cyclin A, as well as the prognostic value of cyclin A overexpression, was affected by gene amplification of cyclin E. Gene amplification of none of the other cyclins was associated with patient prognosis. There was a statistical significant correlation between TP53 gene mutations and gene amplification of cyclins A, D3 and B1. No correlation was observed between gene amplification of secondary cyclins (H and C) and TP53 gene mutations. Conclusions: The overexpression of cyclin A is correlated to gene amplification of both cyclin A and cyclin E. Over-expression of cyclin A is associated with poor prognosis in breast cancer patients. When analysed in a multivariate analyses model, gene amplification as well as protein expression of none of the other cyclins than cyclin A are associated with patient prognosis in breast carcinomas. TP53 gene mutation seems to correlate with gene amplification of primary, but not secondary cyclins.
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Ye, Xiang S., Gang Xu, Robert T. Pu, Russell R. Fincher, Aysha H. Osmani, and Stephen A. Osmani. "Analysis of cell cycle regulation using Aspergillus nidulans." Canadian Journal of Botany 73, S1 (December 31, 1995): 359–63. http://dx.doi.org/10.1139/b95-268.
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Aspergillus nidulans has proved to be an excellent model system to help unravel the genetic and biochemical control systems that regulate the cell cycle. Many genes that specifically affect progression through G2 into mitosis have been isolated. Study of these genes has helped to formulate concepts about how the cell cycle is regulated. The existence of regulatory networks involving protein phosphorylation and dephosphorylation has been realized, and how the kinases and phosphatases of these networks ensure correct order and timing through the cell cycle is beginning to be understood. Our studies indicate that activation of two protein kinases is essential for progression into mitosis. One, the universal p34cdc2 H1 kinase, has been well studied in many systems and is considered the key activator of mitotic initiation. However, in the absence of the NIMA protein kinase p34cdc2 cannot promote mitosis. How these two mitotic kinases interact is therefore of great importance to our understanding of cell cycle regulation. The contribution of studies using A. nidulans to the formulation of concepts about how the cell cycle is regulated is the topic of this paper. Key words: Aspergillus nidulans, cell cycle regulation, protein kinase, NIMA, p34cdc2, cyclinB, Cdc25.
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Xu, Huitao, Adnan Khan, Shanjiang Zhao, Huan Wang, Huiying Zou, Yunwei Pang, and Huabin Zhu. "Effects of Inhibin A on Apoptosis and Proliferation of Bovine Granulosa Cells." Animals 10, no. 2 (February 24, 2020): 367. http://dx.doi.org/10.3390/ani10020367.
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Inhibin A is well known for its inhibitory properties against follicle-stimulating hormone (FSH), released through a pituitary–gonadal negative feedback loop to regulate follicular development. Ovarian folliculogenesis, hormonal biosynthesis, and gametogenesis are dependent on inhibins, playing vital roles in promoting or inhibiting cell proliferation. The present study explored the physiological and molecular response of bovine granulosa cells (GCs) to different concentrations of inhibin A in vitro. We treated the primary GCs isolated from ovarian follicles (3–6 mm) with different levels of inhibin A (20, 50, and 100 ng/mL) along with the control (0 ng/mL) for 24 h. To evaluate the impact of inhibin A on GCs, several in vitro cellular parameters, including cell apoptosis, viability, cell cycle, and mitochondrial membrane potential (MMP) were detected. Besides, the transcriptional regulation of pro-apoptotic (BAX, Caspase-3) and cell proliferation (PCNA, CyclinB1) genes were also quantified. The results indicated a significant (p < 0.05) increase in the cell viability in a dose-dependent manner of inhibin A. Likewise, MMP was significantly (p < 0.05) enhanced when GCs were treated with high doses (50, 100 ng/mL) of inhibin A. Furthermore, inhibin A dose (100 ng/mL) markedly improved the progression of the G1 phase of the cell cycle and increased the cell number in the S phase, which was supported by the up-regulation of the proliferating cell nuclear antigen PCNA (20, 50, and 100ng/mL) and CyclinB (100 ng/mL) genes. In addition, higher doses of inhibin A (50 and 100 ng/mL) significantly (p < 0.05) decreased the apoptotic rate in GCs, which was manifested by down regulating BAX and Caspase-3 genes. Conclusively, our study presented a worthy strategy for the first time to characterize the cellular adaptation of bovine GCs under different concentrations of inhibin A. Our results conclude that inhibin A is a broad regulatory marker in GCs by regulating apoptosis and cellular progression.
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Stiffler, L. A., J. Y. Ji, S. Trautmann, C. Trusty, and G. Schubiger. "Cyclin A and B functions in the early Drosophila embryo." Development 126, no. 23 (December 1, 1999): 5505–13. http://dx.doi.org/10.1242/dev.126.23.5505.
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In eukaryotes, mitotic cyclins localize differently in the cell and regulate different aspects of the cell cycle. We investigated the relationship between subcellular localization of cyclins A and B and their functions in syncytial preblastoderm Drosophila embryos. During early embryonic cycles, cyclin A was always concentrated in the nucleus and present at a low level in the cytoplasm. Cyclin B was predominantly cytoplasmic, and localized within nuclei only during late prophase. Also, cyclin B colocalized with metaphase but not anaphase spindle microtubules. We changed maternal gene doses of cyclins A and B to test their functions in preblastoderm embryos. We observed that increasing doses of cyclin B increased cyclin B-Cdk1 activity, which correlated with shorter microtubules and slower microtubule-dependent nuclear movements. This provides in vivo evidence that cyclin B-Cdk1 regulates microtubule dynamics. In addition, the overall duration of the early nuclear cycles was affected by cyclin A but not cyclin B levels. Taken together, our observations support the hypothesis that cyclin B regulates cytoskeletal changes while cyclin A regulates the nuclear cycles. Varying the relative levels of cyclins A and B uncoupled the cytoskeletal and nuclear events, so we speculate that a balance of cyclins is necessary for proper coordination during these embryonic cycles.
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Ježek, Jan, Daniel G. J. Smethurst, David C. Stieg, Z. A. C. Kiss, Sara E. Hanley, Vidyaramanan Ganesan, Kai-Ti Chang, Katrina F. Cooper, and Randy Strich. "Cyclin C: The Story of a Non-Cycling Cyclin." Biology 8, no. 1 (January 4, 2019): 3. http://dx.doi.org/10.3390/biology8010003.
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The class I cyclin family is a well-studied group of structurally conserved proteins that interact with their associated cyclin-dependent kinases (Cdks) to regulate different stages of cell cycle progression depending on their oscillating expression levels. However, the role of class II cyclins, which primarily act as transcription factors and whose expression remains constant throughout the cell cycle, is less well understood. As a classic example of a transcriptional cyclin, cyclin C forms a regulatory sub-complex with its partner kinase Cdk8 and two accessory subunits Med12 and Med13 called the Cdk8-dependent kinase module (CKM). The CKM reversibly associates with the multi-subunit transcriptional coactivator complex, the Mediator, to modulate RNA polymerase II-dependent transcription. Apart from its transcriptional regulatory function, recent research has revealed a novel signaling role for cyclin C at the mitochondria. Upon oxidative stress, cyclin C leaves the nucleus and directly activates the guanosine 5’-triphosphatase (GTPase) Drp1, or Dnm1 in yeast, to induce mitochondrial fragmentation. Importantly, cyclin C-induced mitochondrial fission was found to increase sensitivity of both mammalian and yeast cells to apoptosis. Here, we review and discuss the biology of cyclin C, focusing mainly on its transcriptional and non-transcriptional roles in tumor promotion or suppression.
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Kreutzer, M. A., J. P. Richards, M. N. De Silva-Udawatta, J. J. Temenak, J. A. Knoblich, C. F. Lehner, and K. L. Bennett. "Caenorhabditis elegans cyclin A- and B-type genes: a cyclin A multigene family, an ancestral cyclin B3 and differential germline expression." Journal of Cell Science 108, no. 6 (June 1, 1995): 2415–24. http://dx.doi.org/10.1242/jcs.108.6.2415.
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We have cloned cDNAs for Caenorhabditis elegans cyclins A1, B and B3. While cyclins A1 and B are most closely related to either A- or B-type cyclins of other species, cyclin B3 is less related to these cyclins. However, this cyclin is most similar to the recently identified chicken cyclin B3. Our identification of a Caenorhabditis homolog demonstrates that cyclin B3 has been conserved in evolution. Cyclin A1 is a member of an A-type multigene family; however the cyclin A1 cDNA only recognizes a single band on northern blots. A single-sized RNA is also observed for the cyclin B3 cDNA. In contrast, three different transcripts are observed for the cyclin B cDNA. Based on our analyses using RNAs from germline-defective mutants and from populations enriched for males, one cyclin B transcript is specific to the paternal germline. The two other cyclin B transcripts, as well as the cyclin A1 and cyclin B3 transcripts, are most abundant in the maternal germline and are only present at low levels in other tissues. Moreover, the 3′ untranslated regions of each Caenorhabditis cyclin cDNA possess several copies of potential translational control elements shown in Xenopus and Drosophila maternal cyclin mRNAs to function during oogenesis and early embryogenesis.
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Geng, Yan, Wojciech Michowski, Joel M. Chick, Yaoyu E. Wang, M. Emmanuelle Jecrois, Katharine E. Sweeney, Lijun Liu, et al. "Kinase-independent function of E-type cyclins in liver cancer." Proceedings of the National Academy of Sciences 115, no. 5 (January 16, 2018): 1015–20. http://dx.doi.org/10.1073/pnas.1711477115.
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E-type cyclins (cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E cyclins are thought to drive tumor cell proliferation by activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma, and this event is associated with strong up-regulation of cyclin E1 expression. Regardless of the underlying mechanism of tumorigenesis, the majority of liver cancers overexpress E-type cyclins. Here we used conditional cyclin E knockout mice and a liver cancer model to test the requirement for the function of E cyclins in liver tumorigenesis. We show that a ubiquitous, global shutdown of E cyclins did not visibly affect postnatal development or physiology of adult mice. However, an acute ablation of E cyclins halted liver cancer progression. We demonstrated that also human liver cancer cells critically depend on E cyclins for proliferation. In contrast, we found that the function of the cyclin E catalytic partner, CDK2, is dispensable in liver cancer cells. We observed that E cyclins drive proliferation of tumor cells in a CDK2- and kinase-independent mechanism. Our study suggests that compounds which degrade or inhibit cyclin E might represent a highly selective therapeutic strategy for patients with liver cancer, as these compounds would selectively cripple proliferation of tumor cells, while sparing normal tissues.
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Carthon, Bradley C., Carola A. Neumann, Manjusri Das, Basil Pawlyk, Tiansen Li, Yan Geng, and Piotr Sicinski. "Genetic Replacement of Cyclin D1 Function in Mouse Development by Cyclin D2." Molecular and Cellular Biology 25, no. 3 (February 1, 2005): 1081–88. http://dx.doi.org/10.1128/mcb.25.3.1081-1088.2005.
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ABSTRACT D cyclins (D1, D2, and D3) are components of the core cell cycle machinery in mammalian cells. It is unclear whether each of the D cyclins performs unique, tissue-specific functions or the three proteins have virtually identical functions and differ mainly in their pattern of expression. We previously generated mice lacking cyclin D1, and we observed that these animals displayed hypoplastic retinas and underdeveloped mammary glands and a presented developmental neurological abnormality. We now asked whether the specific requirement for cyclin D1 in these tissues reflected a unique pattern of D cyclin expression or the presence of specialized functions for cyclin D1 in cyclin D1-dependent compartments. We generated a knock-in strain of mice expressing cyclin D2 in place of D1. Cyclin D2 was able to drive nearly normal development of retinas and mammary glands, and it partially replaced cyclin D1's function in neurological development. We conclude that the differences between these two D cyclins lie mostly in the tissue-specific pattern of their expression. However, we propose that subtle differences between the two D cyclins do exist and they may allow D cyclins to function in a highly optimized fashion. We reason that the acquisition of multiple D cyclins may allow mammalian cells to drive optimal proliferation of a diverse array of cell types.
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Resnitzky, D., and S. I. Reed. "Different roles for cyclins D1 and E in regulation of the G1-to-S transition." Molecular and Cellular Biology 15, no. 7 (July 1995): 3463–69. http://dx.doi.org/10.1128/mcb.15.7.3463.
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Ectopic expression of cyclins D1 and E was previously shown to accelerate the G1/S-phase transition, indicating that both classes of G1 cyclin control an event(s) that is rate limiting for entry into S phase. In order to determine whether cyclins D1 and E control the same or two different rate-limiting events, we have created cell lines that express both cyclins in an inducible manner. We show here that ectopic expression of both cyclins E and D1 in the same cell has an additive effect on shortening of the G1 interval relative to expression of any single cyclin. In order to further explore the molecular basis for G1 cyclin action, we used cell lines capable of expressing cyclin D1, E, or both prematurely and measured the effect of cyclin expression in early G1 on phosphorylation of the retinoblastoma susceptibility gene product (pRb). We show here that while premature expression of either cyclin alone advances the G1/S-phase transition to the same extent, premature expression of cyclin D1 leads to immediate appearance of hyperphosphorylated pRb, while premature expression of cyclin E does not. Ectopic expression of both cyclins E and D1 in the same cell has an additive effect on shortening of the G1 interval, while the effect on pRb phosphorylation is similar to the effect of cyclin D1 alone. These results suggest that cyclins E and D1 control two different events, both rate limiting for the G1/S-phase transition, and that pRb phosphorylation might be the rate-limiting event controlled by cyclin D1.
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Laman, Heike, Dawn Coverley, Torsten Krude, Ronald Laskey, and Nic Jones. "Viral Cyclin–Cyclin-Dependent Kinase 6 Complexes Initiate Nuclear DNA Replication." Molecular and Cellular Biology 21, no. 2 (January 15, 2001): 624–35. http://dx.doi.org/10.1128/mcb.21.2.624-635.2001.
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ABSTRACT The cyclins encoded by Kaposi sarcoma-associated herpesvirus and herpesvirus saimiri are homologs of human D-type cyclins. However, when complexed to cdk6, they have several activities that distinguish them from D-type cyclin-cdk6 complexes, including resistance to cyclin-dependent kinase inhibitors and an enhanced substrate range. We find that viral cyclins interact with and phosphorylate proteins involved in replication initiation. Using mammalian in vitro replication systems, we show that viral cyclin-cdk6 complexes can directly trigger the initiation of DNA synthesis in isolated late-G1-phase nuclei. Viral cyclin-cdk6 complexes share this capacity with cyclin A-cdk2, demonstrating that in addition to functioning as G1-phase cyclin-cdk complexes, they function as S-phase cyclin-cdk complexes.
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El Dika, Mohammed, Lisa Wechselberger, Bilal Djeghout, Djamel Eddine Benouareth, Mohammed El Dika, Lisa Wechselberger, Bilal Djeghout, et al. "Mitotic timing is differentially controlled by A- and B-type cyclins and by CDC6 associated with a bona fide CDK inhibitor Xic1 in Xenopus laevis cell-free extract." International Journal of Developmental Biology 65, no. 7-8-9 (2021): 487–96. http://dx.doi.org/10.1387/ijdb.200313jk.
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The timing of the M-phase is precisely controlled by a CDC6-dependent mechanism inhibiting the mitotic histone H1 kinase. Here, we describe the differential regulation of the dynamics of this mitotic kinase activity by exogenous cyclin A or cyclin B in the Xenopus laevis cycling extracts. We show that the experimental increase in cyclin A modifies only the level of histone H1 kinase activity, while the cyclin B increase modifies two parameters: histone H1 kinase activity and the timing of its full activation, which is accelerated. On the other hand, the cyclin A depletion significantly delays full activation of histone H1 kinase. However, when CDC6 is added to such an extract, it inhibits cyclin B-associated histone H1 kinase, but does not modify the mitotic timing in the absence of cyclin A. Further, we show via p9 co-precipitation with Cyclin-Dependent Kinases (CDKs), that both CDC6 and the bona fide CDK1 inhibitor Xic1 associate with the mitotic CDKs. Finally, we show that the Xic1 temporarily separates from the mitotic CDKs complexes during the peak of histone H1 kinase activity. These data show the differential coordination of the M-phase progression by cyclin A- and cyclin B-dependent CDKs, confirm the critical role of the CDC6-dependent histone H1 kinase inhibition in this process, and show that CDC6 acts differentially through the cyclin B- and cyclin A-associated CDKs. This CDC6- and cyclins-dependent mechanism likely depends on the precisely regulated association of Xic1 with the mitotic CDKs complexes. We postulate that: i. the dissociation of Xic1 from the CDKs complexes allows the maximal activation of CDK1 during the M-phase, ii. the switch between cyclin A- and cyclin B-CDK inhibition upon M-phase initiation may be responsible for the diauxic growth of mitotic histone H1 kinase activity.
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van Dyk, Linda F., Jay L. Hess, Jonathan D. Katz, Meagan Jacoby, Samuel H. Speck, and Herbert W. Virgin. "The Murine Gammaherpesvirus 68 v-Cyclin Gene Is an Oncogene That Promotes Cell Cycle Progression in Primary Lymphocytes." Journal of Virology 73, no. 6 (June 1, 1999): 5110–22. http://dx.doi.org/10.1128/jvi.73.6.5110-5122.1999.
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ABSTRACT Several gammaherpesviruses contain open reading frames encoding proteins homologous to mammalian D-type cyclins. In this study, we analyzed the expression and function of the murine gammaherpesvirus 68 (γHV68) viral cyclin (v-cyclin). The γHV68 v-cyclin gene was expressed in lytically infected fibroblasts as a leaky-late mRNA of approximately 0.9 kb encoding a protein of approximately 25 kDa. To evaluate the effect of the γHV68 v-cyclin on cell cycle progression in primary lymphocytes and to determine if the γHV68 v-cyclin gene is an oncogene, we generated transgenic mice by using the lckproximal promoter to express the γHV68 v-cyclin in early T cells. Expression of the γHV68 v-cyclin significantly increased the number of thymocytes in cell culture, as determined by measuring both DNA content and incorporation of 5-bromo-2-deoxyuridine following in vivo pulse-labeling. Expression of the γHV68 v-cyclin interfered with normal thymocyte maturation, as shown by increased numbers of CD4+ CD8+ double-positive thymocytes and decreased numbers of CD4+ or CD8+single-positive and T-cell-receptor-bright thymocytes and splenocytes in transgenic mice. Despite increased numbers of cycling thymocytes, γHV68–v-cyclin–transgenic mice did not have proportionately increased thymocyte numbers, and staining by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling demonstrated increased apoptosis in the thymi of v-cyclin-transgenic mice. Fifteen of 38 γHV68–v-cyclin–transgenic mice developed high-grade lymphoblastic lymphoma between 3 and 12 months of age. We conclude that (i) the γHV68 v-cyclin is expressed as a leaky-late gene in lytically infected cells, (ii) expression of the γHV68 v-cyclin in thymocytes promotes cell cycle progression and inhibits normal T-cell differentiation, and (iii) the γHV68 v-cyclin gene is an oncogene.
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Kenney, Anna Marie, and David H. Rowitch. "Sonic hedgehog Promotes G1 Cyclin Expression and Sustained Cell Cycle Progression in Mammalian Neuronal Precursors." Molecular and Cellular Biology 20, no. 23 (December 1, 2000): 9055–67. http://dx.doi.org/10.1128/mcb.20.23.9055-9067.2000.
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ABSTRACT Sonic hedgehog (Shh) signal transduction via the G-protein-coupled receptor, Smoothened, is required for proliferation of cerebellar granule neuron precursors (CGNPs) during development. Activating mutations in the Hedgehog pathway are also implicated in basal cell carcinoma and medulloblastoma, a tumor of the cerebellum in humans. However, Shh signaling interactions with cell cycle regulatory components in neural precursors are poorly understood, in part because appropriate immortalized cell lines are not available. We have utilized primary cultures from neonatal mouse cerebella in order to determine (i) whether Shh initiates or maintains cell cycle progression in CGNPs, (ii) if G1 regulation by Shh resembles that of classical mitogens, and (iii) whether individual D-type cyclins are essential components of Shh proliferative signaling in CGNPs. Our results indicate that Shh can drive continued cycling in immature, proliferating CGNPs. Shh treatment resulted in sustained activity of the G1 cyclin-Rb axis by regulating levels ofcyclinD1, cyclinD2, and cyclinEmRNA transcripts and proteins. Analysis of CGNPs fromcyclinD1 −/− orcyclinD2 −/− mice demonstrates that the Shh proliferative pathway does not require unique functions ofcyclinD1 or cyclinD2 and that D-type cyclins overlap functionally in this regard. In contrast to many known mitogenic pathways, we show that Shh proliferative signaling is mitogen-activated protein kinase independent. Furthermore, protein synthesis is required for early effects on cyclin gene expression. Together, our results suggest that Shh proliferative signaling promotes synthesis of regulatory factor intermediates that upregulate or maintain cyclin gene expression and activity of the G1cyclin-Rb axis in proliferating granule neuron precursors.
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Scheurlen, I., S. A. Hoffmeister, and H. C. Schaller. "Presence and expression of G2 cyclins in the coelenterate hydra." Journal of Cell Science 109, no. 5 (May 1, 1996): 1063–69. http://dx.doi.org/10.1242/jcs.109.5.1063.
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In hydra all cell-cycle control occurs in the G2/M transition. Cyclins acting at this restriction point in the cell cycle belong to the cyclin A and B families. In agreement with this we isolated cDNAs coding for a cyclin A and a cyclin B from the multiheaded mutant of Chlorohydra viridissima and a cyclin B from Hydra vulgaris. The two B-type cyclins from hydra show 85.6% identity at the amino acid level, and 84.8% at the nucleotide level. The relatedness is less extensive than that found for mammals, e.g. human and mouse, and is evidence that the two hydra species diverged early in evolution. From each hydra species only one B-type cyclin was found, showing equal relatedness to the B1 and B2 subtypes of cyclins, hinting at a role as common ancestor before the split into B1 and B2 cyclins occurred. All three hydra cyclins contain regulation signals typical for G2/M cyclins, such as a ubiquitin destruction box at the amino terminus, needed for rapid degradation of the protein, and translation and polyadenylation elements in the 3′ untranslated region to regulate RNA storage and RNA degradation. In hydra cell-cycle times vary depending on feeding regime and growth conditions. Cyclin B RNA expression was found to precede the daily mitotic rhythm induced by feeding. During head regeneration cyclin B expression showed the expected drop early during regeneration and an increase later. At the cellular level strongest expression of cyclin B RNA and protein was detected in interstitial cells which possess with one day the shortest cell-cycle time in hydra. Epithelial cells with a three-day cell-cycle rhythm showed variable, and differentiated cells no cyclin B expression. Regions of hydra containing high numbers of proliferating cells, such as developing buds exhibited elevated levels of cyclin B expression.
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Royou, Anne, William Sullivan, and Roger Karess. "Cortical recruitment of nonmuscle myosin II in early syncytial Drosophila embryos." Journal of Cell Biology 158, no. 1 (July 8, 2002): 127–37. http://dx.doi.org/10.1083/jcb.200203148.
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The nuclei of early syncytial Drosophila embryos migrate dramatically toward the poles. The cellular mechanisms driving this process, called axial expansion, are unclear, but myosin II activity is required. By following regulatory myosin light chain (RLC)–green fluorescent protein dynamics in living embryos, we observed cycles of myosin recruitment to the cortex synchronized with mitotic cycles. Cortical myosin is first seen in a patch at the anterocentral part of the embryo at cycle 4. With each succeeding cycle, the patch expands poleward, dispersing at the beginning of each mitosis and reassembling at the end of telophase. Each cycle of actin and myosin recruitment is accompanied by a cortical contraction. The cortical myosin cycle does not require microtubules but correlates inversely with Cdc2/cyclinB (mitosis-promoting factor) activity. A mutant RLC lacking inhibitory phosphorylation sites was fully functional with no effect on the cortical myosin cycle, indicating that Cdc2 must be modulating myosin activity by some other mechanism. An inhibitor of Rho kinase blocks the cortical myosin recruitment cycles and provokes a concomitant failure of axial expansion. These studies suggest a model in which cycles of myosin-mediated contraction and relaxation, tightly linked to Cdc2 and Rho kinase activity, are directly responsible for the axial expansion of the syncytial nuclei.
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Lukas, J., H. Müller, J. Bartkova, D. Spitkovsky, A. A. Kjerulff, P. Jansen-Dürr, M. Strauss, and J. Bartek. "DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1." Journal of Cell Biology 125, no. 3 (May 1, 1994): 625–38. http://dx.doi.org/10.1083/jcb.125.3.625.
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The retinoblastoma gene product (pRB) participates in the regulation of the cell division cycle through complex formation with numerous cellular regulatory proteins including the potentially oncogenic cyclin D1. Extending the current view of the emerging functional interplay between pRB and D-type cyclins, we now report that cyclin D1 expression is positively regulated by pRB. Cyclin D1 mRNA and protein is specifically downregulated in cells expressing SV40 large T antigen, adenovirus E1A, and papillomavirus E7/E6 oncogene products and this effect requires intact RB-binding, CR2 domain of E1A. Exceptionally low expression of cyclin D1 is also seen in genetically RB-deficient cell lines, in which ectopically expressed wild-type pRB results in specific induction of this G1 cyclin. At the functional level, antibody-mediated cyclin D1 knockout experiments demonstrate that the cyclin D1 protein, normally required for G1 progression, is dispensable for passage through the cell cycle in cell lines whose pRB is inactivated through complex formation with T antigen, E1A, or E7 oncoproteins as well as in cells which have suffered loss-of-function mutations of the RB gene. The requirement for cyclin D1 function is not regained upon experimental elevation of cyclin D1 expression in cells with mutant RB, while reintroduction of wild-type RB into RB-deficient cells leads to restoration of the cyclin D1 checkpoint. These results strongly suggest that pRB serves as a major target of cyclin D1 whose cell cycle regulatory function becomes dispensable in cells lacking functional RB. Based on available data including this study, we propose a model for an autoregulatory feedback loop mechanism that regulates both the expression of the cyclin D1 gene and the activity of pRB, thereby contributing to a G1 phase checkpoint control in cycling mammalian cells.
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Kim, Tae-You, and William G. Kaelin. "Differential Control of Transcription by DNA-bound Cyclins." Molecular Biology of the Cell 12, no. 7 (July 2001): 2207–17. http://dx.doi.org/10.1091/mbc.12.7.2207.
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Different cyclins mediate different cell-cycle transitions. Some cyclins, such as cyclin A and cyclin E, form stable complexes with proteins that bind directly or indirectly to DNA and thus might be recruited to certain regions of the genome at specific times in the cell cycle. Furthermore, cyclins contain structural motifs that are also present in known transcriptional modulators. We found that cyclin A is a potent transcriptional repressor and cyclin E is a potent transcriptional activator when bound to DNA via a heterologous DNA binding domain. The former activity was linked to the integrity of the cyclin A cyclin fold, whereas the latter activity related to the ability of cyclin E to activate cdk2 and recognize substrates. Furthermore, we found that cyclin E, but not cyclin A, activated transcription in a cell-cycle–dependent manner when present in physiological concentrations as an unfused protein. These results suggest that cyclin A and cyclin E intrinsically differ with respect to their ability to modulate transcription when tethered to DNA.
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Müller-Tidow, Carsten, Ping Ji, Sven Diederichs, Jenny Potratz, Nicole Bäumer, Gabriele Köhler, Thomas Cauvet, et al. "The Cyclin A1-CDK2 Complex Regulates DNA Double-Strand Break Repair." Molecular and Cellular Biology 24, no. 20 (October 15, 2004): 8917–28. http://dx.doi.org/10.1128/mcb.24.20.8917-8928.2004.
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ABSTRACT Vertebrates express two A-type cyclins; both associate with and activate the CDK2 protein kinase. Cyclin A1 is required in the male germ line, but its molecular functions are incompletely understood. We observed specific induction of cyclin A1 expression and promoter activity after UV and γ-irradiation which was mediated by p53. cyclin A1 −/− cells showed increased radiosensitivity. To unravel a potential role of cyclin A1 in DNA repair, we performed a yeast triple hybrid screen and identified the Ku70 DNA repair protein as a binding partner and substrate of the cyclin A1-CDK2 complex. DNA double-strand break (DSB) repair was deficient in cyclin A1 −/− cells. Further experiments indicated that A-type cyclins activate DNA DSB repair by mechanisms that depend on CDK2 activity and Ku proteins. Both cyclin A1 and cyclin A2 enhanced DSB repair by homologous recombination, but only cyclin A1 significantly activated nonhomologous end joining. DNA DSB repair was specific for A-type cyclins because cyclin E was ineffective. These findings establish a novel function for cyclin A1 and CDK2 in DNA DSB repair following radiation damage.
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King, R. W., M. Glotzer, and M. W. Kirschner. "Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates." Molecular Biology of the Cell 7, no. 9 (September 1996): 1343–57. http://dx.doi.org/10.1091/mbc.7.9.1343.
Full textAbstract:
Mitotic cyclins are abruptly degraded at the end of mitosis by a cell-cycle-regulated ubiquitin-dependent proteolytic system. To understand how cyclin is recognized for ubiquitin conjugation, we have performed a mutagenic analysis of the destruction signal of mitotic cyclins. We demonstrate that an N-terminal cyclin B segment as short as 27 residues, containing the 9-amino-acid destruction box, is sufficient to destabilize a heterologous protein in mitotic Xenopus extracts. Each of the three highly conserved residues of the cyclin B destruction box is essential for ubiquitination and subsequent degradation. Although an intact destruction box is essential for the degradation of both A- and B-type cyclins, we find that the Xenopus cyclin A1 destruction box cannot functionally substitute for its B-type counterpart, because it does not contain the highly conserved asparagine necessary for cyclin B proteolysis. Physical analysis of ubiquitinated cyclin B intermediates demonstrates that multiple lysine residues function as ubiquitin acceptor sites, and mutagenic studies indicate that no single lysine residue is essential for cyclin B degradation. This study defines the key residues of the destruction box that target cyclin for ubiquitination and suggests there are important differences in the way in which A- and B-type cyclins are recognized by the cyclin ubiquitination machinery.
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Nascimento, R., J. D. Dias, and R. M. E. Parkhouse. "The conserved UL24 family of human alpha, beta and gamma herpesviruses induces cell cycle arrest and inactivation of the cyclinB/cdc2 complex." Archives of Virology 154, no. 7 (June 13, 2009): 1143–49. http://dx.doi.org/10.1007/s00705-009-0420-y.
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Roberts, J. M., A. Koff, K. Polyak, E. Firpo, S. Collins, M. Ohtsubo, and J. Massague. "Cyclins, Cdks, and Cyclin Kinase Inhibitors." Cold Spring Harbor Symposia on Quantitative Biology 59 (January 1, 1994): 31–38. http://dx.doi.org/10.1101/sqb.1994.059.01.006.
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Diehl, J. Alan. "Cycling to Cancer with Cyclin D1." Cancer Biology & Therapy 1, no. 3 (May 5, 2002): 226–31. http://dx.doi.org/10.4161/cbt.72.
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Gao, Chun Y., and Peggy S. Zelenka. "Cyclins, cyclin-dependent kinases and differentiation." BioEssays 19, no. 4 (April 1997): 307–15. http://dx.doi.org/10.1002/bies.950190408.
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Jung, J. U., M. Stäger, and R. C. Desrosiers. "Virus-encoded cyclin." Molecular and Cellular Biology 14, no. 11 (November 1994): 7235–44. http://dx.doi.org/10.1128/mcb.14.11.7235-7244.1994.
Full textAbstract:
Herpesvirus saimiri contains an open reading frame called eclf2 with homology to the cellular type D cyclins. We now show that the eclf2 gene product is a novel virus-encoded cyclin (v-cyclin). The protein encoded by the v-cyclin gene of this oncogenic herpesvirus was found to have an apparent molecular size of 29 kDa in transformed cells. v-Cyclin protein was found to be associated with cdk6, a cellular cyclin-dependent kinase known to interact with cellular type D cyclins. cdk6/v-cyclin complexes strongly phosphorylated Rb fusion protein and histone H1 as substrates in vitro. Mutational analyses showed that highly conserved amino acids in the cyclin box of v-cyclin were important for association with cdk6 and for activation of cdk6 kinase activity. Thus, v-cyclin resembles cellular type D cyclins in primary sequence, in its association with cdk6, by its ability to activate protein kinase activity, and by the presence of functional cyclin box sequences. v-Cyclin exhibited a selective preference for association with cdk6 over other cyclin-dependent kinases and a high level of kinase activation. The properties of v-cyclin suggest a likely role in oncogenic transformation by this T-lymphotropic herpesvirus.
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Jung, J. U., M. Stäger, and R. C. Desrosiers. "Virus-encoded cyclin." Molecular and Cellular Biology 14, no. 11 (November 1994): 7235–44. http://dx.doi.org/10.1128/mcb.14.11.7235.
Full textAbstract:
Herpesvirus saimiri contains an open reading frame called eclf2 with homology to the cellular type D cyclins. We now show that the eclf2 gene product is a novel virus-encoded cyclin (v-cyclin). The protein encoded by the v-cyclin gene of this oncogenic herpesvirus was found to have an apparent molecular size of 29 kDa in transformed cells. v-Cyclin protein was found to be associated with cdk6, a cellular cyclin-dependent kinase known to interact with cellular type D cyclins. cdk6/v-cyclin complexes strongly phosphorylated Rb fusion protein and histone H1 as substrates in vitro. Mutational analyses showed that highly conserved amino acids in the cyclin box of v-cyclin were important for association with cdk6 and for activation of cdk6 kinase activity. Thus, v-cyclin resembles cellular type D cyclins in primary sequence, in its association with cdk6, by its ability to activate protein kinase activity, and by the presence of functional cyclin box sequences. v-Cyclin exhibited a selective preference for association with cdk6 over other cyclin-dependent kinases and a high level of kinase activation. The properties of v-cyclin suggest a likely role in oncogenic transformation by this T-lymphotropic herpesvirus.