RESUMO
Racecar drivers use left-foot braking, i.e., simultaneously engaging brake and throttle, to carefully balance acceleration and traction when navigating chicanes. In this issue, Lara-Gonzalez et al. (https://doi.org/10.1083/jcb.202308034) show that C. elegans embryos employ the molecular equivalent of left-foot braking to faithfully speed through mitosis.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mitose , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Ciclina B/metabolismo , Ciclina B/genéticaRESUMO
The centrosome of the amoebozoan model Dictyostelium discoideum provides the best-established model for an acentriolar centrosome outside the Opisthokonta. Dictyostelium exhibits an unusual centrosome cycle, in which duplication is initiated only at the G2/M transition and occurs entirely during the M phase. Little is known about the role of conserved centrosomal kinases in this process. Therefore, we have generated knock-in strains for Aurora (AurK), CDK1, cyclin B, Nek2, and Plk, replacing the endogenous genes with constructs expressing the respective green fluorescent Neon fusion proteins, driven by the endogenous promoters, and studied their behavior in living cells. Our results show that CDK1 and cyclin B arrive at the centrosome first, already during G2, followed by Plk, Nek2, and AurK. Furthermore, CDK1/cyclin B and AurK were dynamically localized at kinetochores, and AurK in addition at nucleoli. The putative roles of all four kinases in centrosome duplication, mitosis, cytokinesis, and nucleolar dynamics are discussed.
Assuntos
Proteína Quinase CDC2 , Centrossomo , Dictyostelium , Mitose , Centrossomo/metabolismo , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/genética , Dictyostelium/genética , Dictyostelium/metabolismo , Dictyostelium/enzimologia , Quinases Relacionadas a NIMA/metabolismo , Quinases Relacionadas a NIMA/genética , Ciclina B/metabolismo , Ciclina B/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Cinetocoros/metabolismo , Aurora Quinases/metabolismo , Aurora Quinases/genética , Nucléolo Celular/metabolismoRESUMO
Positive feedback loops exist in many biological circuits important for organismal function. In this work, we investigate how temporal delay affects the dynamics of two canonical positive feedback models. We consider models of a genetic toggle switch and a one-way switch with delay added to the feedback terms. We show that long-lasting transient oscillations exist in both models under general conditions and that the duration depends strongly on the magnitude of the delay and initial conditions. We then show the existence of long-lasting oscillations in specific biological examples: the Cdc2-Cyclin B/Wee1 system and a genetic regulatory network. Our results challenge fundamental assumptions underlying oscillatory behavior in biological systems. While generally delayed negative feedback systems are canonical in generating oscillations, we show that delayed positive feedback systems are a mechanism for generating oscillations as well.
Assuntos
Retroalimentação Fisiológica , Redes Reguladoras de Genes , Modelos Biológicos , Ciclina B/metabolismo , Proteína Quinase CDC2/metabolismoRESUMO
Mitosis in early embryos often proceeds at a rapid pace, but how this pace is achieved is not understood. Here, we show that cyclin B3 is the dominant driver of rapid embryonic mitoses in the C. elegans embryo. Cyclins B1 and B2 support slow mitosis (NEBD to anaphase â¼600 s), but the presence of cyclin B3 dominantly drives the approximately threefold faster mitosis observed in wildtype. Multiple mitotic events are slowed down in cyclin B1 and B2-driven mitosis, and cyclin B3-associated Cdk1 H1 kinase activity is â¼25-fold more active than cyclin B1-associated Cdk1. Addition of cyclin B1 to fast cyclin B3-only mitosis introduces an â¼60-s delay between completion of chromosome alignment and anaphase onset; this delay, which is important for segregation fidelity, is dependent on inhibitory phosphorylation of the anaphase activator Cdc20. Thus, cyclin B3 dominance, coupled to a cyclin B1-dependent delay that acts via Cdc20 phosphorylation, sets the rapid pace and ensures mitotic fidelity in the early C. elegans embryo.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Ciclina B1 , Embrião não Mamífero , Mitose , Animais , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/genética , Proteínas Cdc20/metabolismo , Proteínas Cdc20/genética , Ciclina B/metabolismo , Ciclina B/genética , Ciclina B1/metabolismo , Ciclina B1/genética , Ciclina B2/metabolismo , Ciclina B2/genética , Embrião não Mamífero/metabolismo , FosforilaçãoAssuntos
Ciclina D1 , Neoplasias Renais , Sarcoma de Células Claras , Humanos , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Sarcoma de Células Claras/metabolismo , Masculino , Neoplasias Renais/genética , Neoplasias Renais/patologia , Feminino , Criança , Pré-Escolar , Lactente , Prognóstico , Taxa de Sobrevida , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Recidiva Local de Neoplasia , Imuno-Histoquímica , Estadiamento de Neoplasias , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Fusão Oncogênica/genética , Ciclina BRESUMO
The ATP-dependent phosphorylation activity of cyclin-dependent kinase 1 (CDK1), an essential enzyme for cell cycle progression, is regulated by interactions with Cyclin-B, substrate, and Cks proteins. We have recently shown that active site acetylation in CDK1 abrogated binding to Cyclin-B which posits an intriguing long-range communication between the catalytic site and the protein-protein interaction (PPI) interface. Now, we demonstrate a general allosteric link between the CDK1 active site and all three of its PPI interfaces through atomistic molecular dynamics (MD) simulations. Specifically, we examined ATP binding free energies to CDK1 in native nonacetylated (K33wt) and acetylated (K33Ac) forms as well as the acetyl-mimic K33Q and the acetyl-null K33R mutant forms, which are accessible in vitro. In agreement with experiments, ATP binding is stronger in K33wt relative to the other three perturbed states. Free energy decomposition reveals, in addition to expected local changes, significant and selective nonlocal entropic responses to ATP binding/perturbation of K33 from the αC -helix, activation loop (A-loop), and αG - α H segments in CDK1 which interface with Cyclin-B, substrate, and Cks proteins, respectively. Statistical analysis reveals that while entropic responses of protein segments to active site perturbations are on average correlated with their dynamical changes, such correlations are lost in about 9%-48% of the dataset depending on the segment. Besides proving the bi-directional communication between the active site and the CDK1:Cyclin-B interface, our study uncovers a hitherto unknown mode of ATP binding regulation by multiple PPI interfaces in CDK1.
Assuntos
Trifosfato de Adenosina , Proteína Quinase CDC2 , Simulação de Dinâmica Molecular , Ligação Proteica , Proteína Quinase CDC2/metabolismo , Proteína Quinase CDC2/química , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/química , Regulação Alostérica , Humanos , Domínio Catalítico , Fosforilação , Termodinâmica , Ciclina B/metabolismo , Ciclina B/química , Sítios de Ligação , Domínios e Motivos de Interação entre ProteínasRESUMO
The study of the physiological and pathophysiological processes under extreme conditions facilitates a better understanding of the state of a healthy organism and can also shed light on the pathogenesis of diseases. In recent years, it has become evident that gravitational stress affects both the whole organism and individual cells. We have previously demonstrated that simulated microgravity inhibits proliferation, induces apoptosis, changes morphology, and alters the surface marker expression of megakaryoblast cell line MEG-01. In the present work, we investigate the expression of cell cycle cyclins in MEG-01 cells. We performed several experiments for 24 h, 72 h, 96 h and 168 h. Flow cytometry and Western blot analysis demonstrated that the main change in the levels of cyclins expression occurs under conditions of simulated microgravity after 96 h. Thus, the level of cyclin A expression showed an increase in the RPM group during the first 4 days, followed by a decrease, which, together with the peak of cyclin D, may indicate inhibition of the cell cycle in the G2 phase, before mitosis. In addition, based on the data obtained by PCR analysis, we were also able to see that both cyclin A and cyclin B expression showed a peak at 72 h, followed by a gradual decrease at 96 h. STED microscopy data also confirmed that the main change in cyclin expression of MEG-01 cells occurs at 96 h, under simulated microgravity conditions, compared to static control. These results suggested that the cell cycle disruption induced by RPM-simulated microgravity in MEG-01 cells may be associated with the altered expression of the main regulators of the cell cycle. Thus, these data implicate the development of cellular stress in MEG-01 cells, which may be important for proliferating human cells exposed to microgravity in real space.
Assuntos
Ciclo Celular , Ciclinas , Simulação de Ausência de Peso , Humanos , Linhagem Celular , Ciclinas/metabolismo , Ciclinas/genética , Células Progenitoras de Megacariócitos/metabolismo , Células Progenitoras de Megacariócitos/citologia , Ciclina A/metabolismo , Ciclina A/genética , Proliferação de Células , Ciclina B/metabolismo , Ciclina B/genéticaRESUMO
In human cells and yeast, an intact "hydrophobic patch" substrate docking site is needed for mitotic cyclin centrosomal localization. A hydrophobic patch mutant (HPM) of the fission yeast mitotic cyclin Cdc13 cannot enter mitosis, but whether this is due to defective centrosomal localization or defective cyclin-substrate docking more widely is unknown. Here, we show that artificially restoring Cdc13-HPM centrosomal localization promotes mitotic entry and increases CDK (cyclin-dependent kinase) substrate phosphorylation at the centrosome and in the cytoplasm. We also show that the S-phase B-cyclin hydrophobic patch is required for centrosomal localization but not for S phase. We propose that the hydrophobic patch is essential for mitosis due to its requirement for the local concentration of cyclin-CDK with CDK substrates and regulators at the centrosome. Our findings emphasize the central importance of the centrosome as a hub coordinating cell-cycle control and explain why the cyclin hydrophobic patch is essential for mitosis.
Assuntos
Ciclo Celular , Centrossomo , Ciclina B , Quinases Ciclina-Dependentes , Mitose , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Centrossomo/metabolismo , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Fosforilação , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Interações Hidrofóbicas e Hidrofílicas , HumanosAssuntos
Proteínas Correpressoras , Ciclina B , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Sarcoma , Humanos , Masculino , Ciclina B/genética , Ciclina B/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sarcoma/genética , Sarcoma/patologia , Sarcoma/metabolismo , Hibridização in Situ Fluorescente , Diagnóstico Diferencial , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/metabolismo , Imuno-Histoquímica , Adulto , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismoRESUMO
Abscission is the final step of cytokinesis that allows the physical separation of sister cells through the scission of the cellular membrane. This deformation is driven by ESCRT-III proteins, which can bind membranes and form dynamic helices. A crucial step in abscission is the recruitment of ESCRT-III proteins at the right time and place. Alix is one of the best characterized proteins that recruits ESCRT-III proteins from yeast to mammals. However, recent studies in vivo have revealed that pathways acting independently or redundantly with Alix are also required at abscission sites in different cellular contexts. Here, we show that Lgd acts redundantly with Alix to properly localize ESCRT-III to the abscission site in germline stem cells (GSCs) during Drosophila oogenesis. We further demonstrate that Lgd is phosphorylated at multiple sites by the CycB/Cdk1 kinase. We found that these phosphorylation events potentiate the activity of Shrub, a Drosophila ESCRT-III, during abscission of GSCs. Our study reveals that redundancy between Lgd and Alix, and coordination with the cell cycle kinase Cdk1, confers robust and timely abscission of Drosophila germline stem cells.
Assuntos
Proteínas de Drosophila , Complexos Endossomais de Distribuição Requeridos para Transporte , Células Germinativas , Células-Tronco , Animais , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Ciclina B , Citocinese/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Células Germinativas/metabolismo , Mamíferos/metabolismo , Células-Tronco/metabolismoRESUMO
Meiosis is a complex variant of the mitotic cell cycle, and as such relies on many of the same proteins involved in mitosis, but utilizes these in novel ways. As in mitosis, Cdk1 and its cyclin partners, Cyclin A, B, and B3 are required at multiple steps in meiosis. Here, we study the effect of stabilized forms of the three mitotic cyclins to study the consequences of failure to degrade the cyclins in meiosis. We find that stabilized Cyclin B3 promotes ectopic microtubule polymerization throughout the egg, dependent on APC/C activity and apparently due to the consequent destruction of Cyclin A and Cyclin B. We present data that suggests CycB, and possibly CycA, can also promote APC/C activity at specific stages of meiosis. We also present evidence that in meiosis APC/CCort and APC/CFzy are able to target Cyclin B via a novel degron. Overall, our findings highlight the distinct functions of the three mitotic Cdk-cyclin complexes in meiosis.
Assuntos
Ciclina B , Ciclinas , Proteínas de Drosophila , Meiose , Mitose , Animais , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Ciclina B/metabolismo , Ciclina B/genética , Ciclinas/metabolismo , Ciclinas/genética , Ciclina A/metabolismo , Drosophila/metabolismo , Drosophila/genética , Microtúbulos/metabolismo , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Ciclossomo-Complexo Promotor de Anáfase/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genéticaRESUMO
Cyclin-dependent kinase 1 (Cdk1) complexed with cyclin B phosphorylates multiple sites on hundreds of proteins during mitosis. However, it is not fully understood how multi-site mitotic phosphorylation by cyclin B-Cdk1 controls the structures and functions of individual substrates. Here we develop an easy-to-use protocol to express recombinant vertebrate cyclin B and Cdk1 in insect cells from a single baculovirus vector and to purify their complexes with excellent homogeneity. A series of in-vitro assays demonstrate that the recombinant cyclin B-Cdk1 can efficiently and specifically phosphorylate the SP and TP motifs in substrates. The addition of Suc1 (a Cks1 homolog in fission yeast) accelerates multi-site phosphorylation of an artificial substrate containing TP motifs. Importantly, we show that mitosis-specific multi-subunit and multi-site phosphorylation of the condensin I complex can be recapitulated in vitro using recombinant cyclin B-Cdk1-Suc1. The materials and protocols described here will pave the way for dissecting the biochemical basis of critical mitotic processes that accompany Cdk1-mediated large-scale phosphorylation.
Assuntos
Proteína Quinase CDC2 , Ciclina B , Proteína Quinase CDC2/metabolismo , Fosforilação , Ciclina B/genética , Ciclina B/metabolismo , Proteínas/metabolismo , MitoseRESUMO
Entry into mitosis has been classically attributed to the activation of a cyclin B/Cdk1 amplification loop via a partial pool of this kinase becoming active at the end of G2 phase. However, how this initial pool is activated is still unknown. Here we discovered a new role of the recently identified PP2A-B55 inhibitor FAM122A in triggering mitotic entry. Accordingly, depletion of the orthologue of FAM122A in C. elegans prevents entry into mitosis in germline stem cells. Moreover, data from Xenopus egg extracts strongly suggest that FAM122A-dependent inhibition of PP2A-B55 could be the initial event promoting mitotic entry. Inhibition of this phosphatase allows subsequent phosphorylation of early mitotic substrates by cyclin A/Cdk, resulting in full cyclin B/Cdk1 and Greatwall (Gwl) kinase activation. Subsequent to Greatwall activation, Arpp19/ENSA become phosphorylated and now compete with FAM122A, promoting its dissociation from PP2A-B55 and taking over its phosphatase inhibition role until the end of mitosis.
Assuntos
Caenorhabditis elegans , Proteínas Serina-Treonina Quinases , Animais , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Mitose , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Ciclina B/metabolismoRESUMO
The cyclin-dependent kinase 1 (Cdk1)-cyclin B (CycB) complex plays critical roles in cell-cycle regulation. Before Drosophila male meiosis, CycB is exported from the nucleus to the cytoplasm via the nuclear porin 62kD (Nup62) subcomplex of the nuclear pore complex. When this export is inhibited, Cdk1 is not activated, and meiosis does not initiate. We investigated the mechanism that controls the cellular localization and activation of Cdk1. Cdk1-CycB continuously shuttled into and out of the nucleus before meiosis. Overexpression of CycB, but not that of CycB with nuclear localization signal sequences, rescued reduced cytoplasmic CycB and inhibition of meiosis in Nup62-silenced cells. Full-scale Cdk1 activation occurred in the nucleus shortly after its rapid nuclear entry. Cdk1-dependent centrosome separation did not occur in Nup62-silenced cells, whereas Cdk1 interacted with Cdk-activating kinase and Twine/Cdc25C in the nuclei of Nup62-silenced cells, suggesting the involvement of another suppression mechanism. Silencing of roughex rescued Cdk1 inhibition and initiated meiosis. Nuclear export of Cdk1 ensured its escape from inhibition by a cyclin-dependent kinase inhibitor. The complex re-entered the nucleus via importin ß at the onset of meiosis. We propose a model regarding the dynamics and activation mechanism of Cdk1-CycB to initiate male meiosis.
Assuntos
Proteínas de Drosophila , Drosophila , Animais , Masculino , Drosophila/metabolismo , Transporte Ativo do Núcleo Celular , Citoplasma/metabolismo , Proteínas de Drosophila/metabolismo , Meiose , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Ciclina B/metabolismoRESUMO
During meiosis, germ cell and stage-specific components impose additional layers of regulation on the core cell cycle machinery to set up an extended G2 period termed meiotic prophase. In Drosophila males, meiotic prophase lasts 3.5â days, during which spermatocytes upregulate over 1800 genes and grow 25-fold. Previous work has shown that the cell cycle regulator Cyclin B (CycB) is subject to translational repression in immature spermatocytes, mediated by the RNA-binding protein Rbp4 and its partner Fest. Here, we show that the spermatocyte-specific protein Lut is required for translational repression of cycB in an 8-h window just before spermatocytes are fully mature. In males mutant for rbp4 or lut, spermatocytes enter and exit meiotic division 6-8â h earlier than in wild type. In addition, spermatocyte-specific isoforms of Syncrip (Syp) are required for expression of CycB protein in mature spermatocytes and normal entry into the meiotic divisions. Lut and Syp interact with Fest independent of RNA. Thus, a set of spermatocyte-specific regulators choreograph the timing of expression of CycB protein during male meiotic prophase.
Assuntos
Proteínas de Drosophila , Meiose , Animais , Masculino , Meiose/genética , Espermatogênese/fisiologia , Prófase , Mitose , Espermatócitos/metabolismo , Drosophila/genética , Ciclina B/genética , Ciclina B/metabolismo , Proteínas de Drosophila/metabolismoRESUMO
Cell cycle progression during development is meticulously coordinated with differentiation. This is particularly evident in the Drosophila 3rd instar eye imaginal disc, where the cell cycle is synchronized and arrests at the G1 phase in the non-proliferative region (NPR), setting the stage for photoreceptor cell differentiation. Here, we identify the transcription factor Nuclear Factor-YC (NF-YC) as a crucial player in this finely tuned progression, elucidating its specific role in the synchronized movement of the morphogenetic furrow. Depletion of NF-YC leads to extended expression of Cyclin A (CycA) and Cyclin B (CycB) from the FMW to the NPR. Notably, NF-YC knockdown resulted in decreased expression of Eyes absent (Eya) but did not affect Decapentaplegic (Dpp) and Hedgehog (Hh). Our findings highlight the role of NF-YC in restricting the expression of CycA and CycB in the NPR, thereby facilitating cell-cycle synchronization. Moreover, we identify the transcriptional cofactor Eya as a downstream target of NF-YC, revealing a new regulatory pathway in Drosophila eye development. This study expands our understanding of NF-YC's role from cell cycle control to encompass developmental processes.
Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Discos Imaginais/metabolismo , Proteínas Hedgehog/metabolismo , Olho/metabolismo , Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Ciclina B/metabolismoRESUMO
BACKGROUND: Oocyte maturation arrest results in female infertility and the genetic etiology of this phenotype remains largely unknown. Previous studies have proven that cyclins play a significant role in the cell cycle both in meiosis and mitosis. Cyclin B3 (CCNB3) is one of the members of the cyclin family and its function in human oocyte maturation is poorly understood. METHODS: 118 infertile patients were recruited and WES was performed for 68 independent females that experienced oocyte maturation arrest. Four mutations in CCNB3 were found and effects of these mutations were validated by Sanger sequencing and in vitro functional analyses. RESULTS: We found these mutations altered the location of cyclin B3 which affected the function of cyclin dependent kinase 1 (CDK1) and led to mouse oocyte arrested at germinal vesicle (GV) stage. And then, low CDK1 activity influenced the degradation of cadherin 1 (CDH1) and the accumulation of cell division cycle 20 (CDC20) which are two types of anaphase-promoting complex/cyclosome (APC/C) activators and act in different stages of the cell cycle. Finally, APC/C activity was downregulated due to insufficient CDC20 level and resulted in oocyte metaphase I (MI) arrest. Moreover, we also found that the addition of PP1 inhibitor Okadic acid and CDK1 inhibitor Roscovitine at corresponding stages during oocyte in vitro maturation (IVM) significantly improved the maturation rates in CCNB3 mutant cRNAs injected oocytes. The above experiments were performed in mouse oocytes. CONCLUSION: Here, we report five independent patients in which mutations in CCNB3 may be the cause of oocyte maturation arrest. Our findings shed lights on the critical role of CCNB3 in human oocyte maturation.
Assuntos
Proteína Quinase CDC2 , Ciclina B , Oócitos , Animais , Feminino , Humanos , Camundongos , Proteína Quinase CDC2/genética , Ciclina B/genética , Meiose/genética , Mutação , FenótipoAssuntos
Fertilização , Meiose , Feminino , Humanos , Meiose/genética , Oócitos , Ciclina B/metabolismoRESUMO
Adult stem cells maintain homeostatic self-renewal through the strategy of either population or single-cell asymmetry, and the former type of stem cells are thought to take passive while the latter ones take active competition for niche occupancy. Although the division ability of stem cells is known to be crucial for their passive competition, whether it is also crucial for active competition is still elusive. Drosophila female germline stem cells are thought to take active competition, and bam mutant germ cells are more competitive than wild-type germline stem cells for niche occupancy. Here we report that either cycB, cycE, cdk2, or rheb null mutation drastically attenuates the division ability and niche occupancy capacity of bam mutant germ cells. Conversely, accelerating their cell cycle by mutating hpo has an enhanced effect. Last but not least, we also determine that E-cadherin, which was proposed to be crucial previously, just plays a mild role in bam mutant germline niche occupancy. Together with previous studies, we propose that division ability plays a unified crucial role in either active or passive competition among stem cells for niche occupancy.
Assuntos
Células-Tronco Adultas , Proteínas de Drosophila , Animais , Feminino , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Transdução de Sinais/genética , Diferenciação Celular/genética , Ovário/metabolismo , Drosophila/genética , Células-Tronco Adultas/metabolismo , Células Germinativas/metabolismo , Nicho de Células-Tronco/genética , Drosophila melanogaster/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ciclina B/metabolismoRESUMO
BACKGROUND BCOR: CCNB3 sarcoma is a rare mesenchymal tumor that was formerly included in the undifferentiated/unclassified sarcoma group and was recently reclassified as one of undifferentiated small round cell sarcomas with a genetically distinct subtype in the WHO 2020 classification. Because of its rarity, still not much is known, especially about its clinical features. CASE REPORT A 15-year-old boy presented with almost 1-year intermittent thigh pain. On the first visit, a pathologic fracture of the femur and a big mass expanding through the femoral cortex with lobular shape and homogenous appearance were recognized on radiography and magnetic resonance imaging. Plain radiography, which was taken 6 months before at a local clinic, showed an expansion and thickening of the right proximal femoral shaft. Biopsy specimen of the lesion revealed a proliferation of round to spindle tumor cells with diffuse and strong immunohistochemical nuclear positivity for BCOR and CCNB3. Under the diagnosis of BCOR::CCNB3 sarcoma of the femur, a chemotherapy based on a protocol of Ewing sarcoma, followed by a wide resection and total femoral replacement surgery, were conducted. The effect of chemotherapy was favorable, showing no microscopic residual tumor. Although postoperative chemotherapy was not completed because of a minor infection detected on the surgical site, the patient was doing well, without any recurrence, for 26 months. CONCLUSIONS BCOR: CCNB3 sarcoma of the bone is a quite rare tumor with much lower incidence than Ewing sarcoma. Notable clinical characteristics of the current case were a 1-year-long symptomatic period and homogenous appearance on MRI.