Objective To investigate the fate and underlying mechanisms of G2 phase arrest in cancer cells elicited by ionizing radiation(IR).Methods Human melanoma A375 and 92-1 cells were treated with X-rays radiation or Aurora...Objective To investigate the fate and underlying mechanisms of G2 phase arrest in cancer cells elicited by ionizing radiation(IR).Methods Human melanoma A375 and 92-1 cells were treated with X-rays radiation or Aurora A inhibitor MLN8237(MLN)and/or p21 depletion by small interfering RNA(si RNA).Cell cycle distribution was determined using flow cytometry and a fluorescent ubiquitin-based cell cycle indicator(FUCCI)system combined with histone H3 phosphorylation at Ser10(p S10 H3)detection.Senescence was assessed using senescence-associated-β-galactosidase(SA-β-Gal),Ki67,andγH2AX staining.Protein expression levels were determined using western blotting.Results Tumor cells suffered severe DNA damage and underwent G2 arrest after IR treatment.The damaged cells did not successfully enter M phase nor were they stably blocked at G2 phase but underwent mitotic skipping and entered G1 phase as tetraploid cells,ultimately leading to senescence in G1.During this process,the p53/p21 pathway is hyperactivated.Accompanying p21 accumulation,Aurora A kinase levels declined sharply.MLN treatment confirmed that Aurora A kinase activity is essential for mitosis skipping and senescence induction.Conclusion Persistent p21 activation during IR-induced G2 phase blockade drives Aurora A kinase degradation,leading to senescence via mitotic skipping.展开更多
Cancer has been an insurmountable problem in the history of medical science.The uncontrollable proliferation of cancer cells is one of cancers main characteristics,which is closely associated with abn ormal mitosis.Ta...Cancer has been an insurmountable problem in the history of medical science.The uncontrollable proliferation of cancer cells is one of cancers main characteristics,which is closely associated with abn ormal mitosis.Targeting mitosis is an effective method for cancer treatment.This review summarizes several natural products with anti-tumor effects related to mitosis,focusing on targeting microtubulin,inducing DNA damage,and modulating mitosis-associated kinases.Furthermore,the main disadvantages of several typical compounds,including drug resistance,toxicity to non-tumor tissues,and poor aqueous solubility and pharmacokinetic properties,are also discussed,together with strategies to address them.Improved understanding of cancer cell mitosis and natural products may pave the way to drug development for the treatment of cancer.展开更多
BACKGROUND Mammary-type myofibroblastoma(MTMF)is a rare benign extramammary soft tissue tumor with myofibroblastic differentiation.Although 160 cases of MTMF have been reported in the literature since 2001,no cases of...BACKGROUND Mammary-type myofibroblastoma(MTMF)is a rare benign extramammary soft tissue tumor with myofibroblastic differentiation.Although 160 cases of MTMF have been reported in the literature since 2001,no cases of infarction or atypical mitosis have been reported so far.Herein,we report an unusual case of MTMF in the pelvic cavity,which mimicked some malignant features,including infarction,atypical mitosis,infiltrative growth,and prominent cytologic atypia,making it difficult to ascertain whether the tumor was benign.CASE SUMMARY A 49-year-old man complained of pain and discomfort in the right buttock for more than 4 mo and did not receive any treatment.Nuclear magnetic resonance imaging(MRI)showed a 13-cm-sized mass in his right pelvic cavity.Histologically significant differences were atypical mitosis figures and multiple necrotic foci in the tumor.In addition,smooth muscle and skeletal muscle were invaded within and at the edge of the tumor.These morphologic features are often reminiscent of malignant tumors and therefore pose a diagnostic challenge to pathologists.The tumor cells were strongly positive for both cluster of differentiation 34 and desmin,and the loss of retinoblastoma 1 shown by immunohistochemical and fluorescence in situ hybridization results confirmed the pathological diagnosis of MTMF.Currently,the patient is alive and in good condition without tumor recurrence or metastasis after 2.5 years of follow-up by telephone and MRI.CONCLUSION The two pseudo-malignant characteristics of infarction and atypical mitosis broaden the morphological lineage of MTMF,a rare mesenchymal tumor.展开更多
Tetraploid induction was carried out by inhibiting mitosis I in fertilized eggs of Chlamys farreri . Mitosis I was blocked with cold shock (5 7℃), Cytochalasin B (0.75 mg/L) and 6 dimethylaminopurine (6 DMAP) (60 75 ...Tetraploid induction was carried out by inhibiting mitosis I in fertilized eggs of Chlamys farreri . Mitosis I was blocked with cold shock (5 7℃), Cytochalasin B (0.75 mg/L) and 6 dimethylaminopurine (6 DMAP) (60 75 mg/L) when 60% fertilized eggs released polar body II at 20℃. At 4 cells embryo stage, the ploidy was determined by counting chromosome number. In control groups, most embryos were diploids (72.22%) and aneuploids (24.78%). In Cytochalasin B, cold shock and 6 DMAP treated groups, tetraploids were respectively 10.51%, 4.08%, and 13.34%; aneuploids were 43.10%, 35.93% and 29.16%,and triploids were 7.84%, 8.52% and 18.33%. At D larva stage, ploidy was determined by flow cytometry (FCM). The ploidy analysis of day 2 larvae showed diploids in control group and also in three treated groups. Juvenile scallops (0.2 0.3cm) which were harvested in two control groups and two CB treated groups were all diploids through checking ploidy individually by FCM.展开更多
The modified approach to conventional Artificial Neural Networks (ANN) described in this paper represents an essential departure from the conventional techniques of structural analysis. It has four main distinguishing...The modified approach to conventional Artificial Neural Networks (ANN) described in this paper represents an essential departure from the conventional techniques of structural analysis. It has four main distinguishing features: 1) it introduces a new simulation algorithm based on the biology;2) it performs relatively simple arithmetic as massively parallel, during analysis of a structure;3) it shows that it is possible to use the application of the modified approach to conventional ANN to solve problems of any complexity in the field of structural analysis;4) the Neural Topologies for Structural Analysis (NTSA) system are recurrent networks and its outputs are connected to its inputs [1] and [2]. In NTSA system the DNA of the neuron mother and daughters would be defined by: 1) the same entry, from the corresponding neuron in the previous layer;2) the same trend vector;3) the same transfer function (purelin). The mother’s neuron and her daughter’s neuron differ only in the connection weight and its output signal.展开更多
Background:Cell division is one of the key roles in the cell development,cell differentiation,embryogenesis and recovery of tissues.Independent studies have shown that spindle alignment during not only asymmetric but ...Background:Cell division is one of the key roles in the cell development,cell differentiation,embryogenesis and recovery of tissues.Independent studies have shown that spindle alignment during not only asymmetric but also symmetric cell divisions is essential展开更多
BACKGROUND Tubulins,building blocks of microtubules,are modified substrates of diverse post-translational modifications including phosphorylation,polyglycylation and polyglutamylation.Polyglutamylation of microtubules...BACKGROUND Tubulins,building blocks of microtubules,are modified substrates of diverse post-translational modifications including phosphorylation,polyglycylation and polyglutamylation.Polyglutamylation of microtubules,catalyzed by enzymes from the tubulin tyrosine ligase-like(TTLL)family,can regulate interactions with molecular motors and other proteins.Due to the diversity and functional importance of microtubule modifications,strict control of the TTLL enzymes has been suggested.AIM To characterize the interaction between never in mitosis gene A-related kinase 5(NEK5)and TTLL4 proteins and the effects of TTLL4 phosphorylation.METHODS The interaction between NEK5 and TTLL4 was identified by yeast two-hybrid screening using the C-terminus of NEK5(a.a.260–708)as bait and confirmed by immunoprecipitation.The phosphorylation sites of TTLL4 were identified by mass spectrometry and point mutations were introduced.RESULTS Here,we show that NEK5 interacts with TTLL4 and regulates its polyglutamylation activity.We further show that NEK5 can also interact with TTLL5 and TTLL7.The silencing of NEK5 increases the levels of polyglutamylation of proteins by increasing the activity of TTLL4.The same effects were observed after the expression of the catalytically inactive form of NEK5.This regulation of TTLL4 activity involves its phosphorylation at Y815 and S1136 amino acid residues.CONCLUSION Our results demonstrate,for the first time,the regulation of TTLL activity through phosphorylation,pointing to NEK5 as a potential effector kinase.We also suggest a general control of tubulin polyglutamylation through NEK family members in human cells.展开更多
The effects of growth factors and calcium concentrations present in different culture media on induction of terminal differentiation were investigated for four different epidermoid carcinoma cell lines, Hela, KB, A431...The effects of growth factors and calcium concentrations present in different culture media on induction of terminal differentiation were investigated for four different epidermoid carcinoma cell lines, Hela, KB, A431, and SCC-25, and their responses determined relative to those elicited by normal human keratinocytes subjected to these culture conditions. Differentiation status was determined cyto-chemically by a validated keratin protein staining method, and by autoradiographic analyses. Growth and differentiation promoting factors that influenced the direction of integrated control of growth and differentiation in normal human keratinocytes were found to be effective for some cell lines but not others. The factors examined were 1) high density arrest in serum-free and serum-containing media, 2) media shifts from high density culture in serum-containing media to low density growth factor-depleted or supplemented serum-free medium, and 3) the concentration of calcium in the media. The extent and degree of differentiation achieved varied among different cell lines depend on the presence or absence of serum, EGF and insulin protein growth factors. Certain growth media appear to sponsor keratin protein, cyto-chemically-detected differentiation, and evidence of quantal mitotic division in low density HeLa cell and SCC25 cell cultures. Epidermoid carcinoma cell lines retain limited capacity to commit to early stages of cell differentiation.展开更多
To explore the clinicopathological features of abound mitosis of the hepatocytes in intrahepatic cholelithiasis.The clinicopathological data of one case diagnosed as intrahepatic cholelithiasis was collected from Yant...To explore the clinicopathological features of abound mitosis of the hepatocytes in intrahepatic cholelithiasis.The clinicopathological data of one case diagnosed as intrahepatic cholelithiasis was collected from Yantai Yuhuangding Hospital and the clinicopathological characters were discussed.A 68-year-old man suffered from the pain in the right upper quadrant and radiology showed multiple stones in the gallbladder and left liver.The images suggested intrahepatic cholelithiasis.The patient received gallbladder and partial hepatectomy.A large number of mitosis was observed and twelve nuclear fissions were found under high magnification,even in some area pathological nuclear fission could be observed in morphology.On the basis of detection in laboratory,the diagnosis of intrahepatic cholelithiasis was made.The patient did not receive any therapy after surgery.The patient was in a good condition after 18 months follow-up.Increased number of hepatic mitosis might be due to the stimulation from stones,hepatic biliary or secondary inflammatory.High index of proliferation should be prevented from the potential misdiagnosis of hepatic tumor.展开更多
In mitosis,accurate chromosome segregation depends on the kinetochore,a supermolecular machinery that couples dynamic spin-dle microtubules to centromeric chromatin.However,the structure–activity relationship of the ...In mitosis,accurate chromosome segregation depends on the kinetochore,a supermolecular machinery that couples dynamic spin-dle microtubules to centromeric chromatin.However,the structure–activity relationship of the constitutive centromere-associated network(CCAN)during mitosis remains uncharacterized.Building on our recent cryo-electron microscopic analyses of human CCAN structure,we investigated how dynamic phosphorylation of human CENP-N regulates accurate chromosome segregation.Our mass spectrometric analyses revealed mitotic phosphorylation of CENP-N by CDK1,which modulates the CENP-L–CENP-N interaction for accurate chromosome segregation and CCAN organization.Perturbation of CENP-N phosphorylation is shown to prevent proper chromosome alignment and activate the spindle assembly checkpoint.These analyses provide mechanistic insight into a previously undefined link between the centromere–kinetochore network and accurate chromosome segregation.展开更多
In this paper,the biological function of PLK-1,the correlation between PLK-1 and tumors,and the latest research progress on PLK-1 inhibitors under study are reviewed,in order to provide references for the research and...In this paper,the biological function of PLK-1,the correlation between PLK-1 and tumors,and the latest research progress on PLK-1 inhibitors under study are reviewed,in order to provide references for the research and development of PLK-1 inhibitors.展开更多
Heterochromatin protein 1α (HP1α)regulates chromatin specification and plasticity during cell fate decision.Different structural determinants account for HP1α Localization and function during cell division cycle.Ou...Heterochromatin protein 1α (HP1α)regulates chromatin specification and plasticity during cell fate decision.Different structural determinants account for HP1α Localization and function during cell division cycle.Our earlier study showed that centromeric Localization of HP1α depends on the epigenetic mark H3K9me3 in interphase,while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors.Here,we identified a PXVXL-containing protein,Ligand-dependent nuclear receptorinteracting factor 1 (LRIF1),which recruits HPla to the centromere of mitotic chromosomes and its interaction with HP1α is essential for accurate chromosome segregation during mitosis.LRIF1 interacts directly with HPla chromoshadow domain via an evolutionariLy conserved PXVXL motif within its C-terminus.Importantly,the LRIF1-HPla interaction is critical for Aurora B activity in the inner centromere.Mutation of PXVXL motif of LRIF1 Leads to defects in HPla centromere targeting and aberrant chromosome segregation.These findings reveal a previously unrecognized direct Link between LRIF1 and HP1α in centromere plasticity control and illustrate the critical role of LRIF1-HP1α interaction in orchestrating accurate cell division.展开更多
As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identi...As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.展开更多
The nuclear lamina is a meshwork of intermediate filament-like fibrils situated immediately subjacent to the inner membrane of the nuclear envelope. Together with other proteinaceous elements such as the nuclear pore ...The nuclear lamina is a meshwork of intermediate filament-like fibrils situated immediately subjacent to the inner membrane of the nuclear envelope. Together with other proteinaceous elements such as the nuclear pore complex, the lamina forms part of the karyoskeleton, or structural framework of the nucleus. The lamina is thought to play a role in anchoring the nuclear envelope, and/or providing attachment sites for interphase chromatin. Mammalian somatic cells commonly contain three major lamins: A, B and C.展开更多
Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromoso...Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromosome segregation.Although a list of mitotic kinases has been implicated in NEBD,how they coordinate their activity to dissolve the nuclear envelope and protein machinery such as nuclear pore complexes was unclear.Here,we identified a regulatory mechanism in which Nup62 is acetylated by TIP60 in human cell division.Nup62 is a novel substrate of TIP60,and the acetylation of Lys432 by TIP60 dissolves nucleoporin Nup62-Nup58-Nup54 complex during entry into mitosis.Importantly,this acetylation-elicited remodeling of nucleoporin complex promotes the distribution of Nup62 to the mitotic spindle,which is indispensable for orchestrating correct spindle orientation.Moreover,suppression of Nup62 perturbs accurate chromosome segregation during mitosis.These results establish a previously uncharacterized regulatory mechanism in which TIP60-elicited nucleoporin dynamics promotes chromosome segregation in mitosis.展开更多
The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogs with Bub1 being a kinase, while BubR1 localizes the PP2A-B56 protein phosphata...The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogs with Bub1 being a kinase, while BubR1 localizes the PP2A-B56 protein phosphatase to kinetochores in humans. Whether this spatial separation of kinase and phosphatase activity is important is unclear as some organisms integrate both activities into one Bub protein. Here, we engineer human Bub1 and BubR1 proteins integrating kinase and phosphatase activities into one protein and show that these do not support normal mitotic progression. A Bub1–PP2A-B56 complex can support chromosome alignment but results in impairment of the checkpoint due to dephosphorylation of the Mad1 binding site in Bub1. Furthermore, a chimeric BubR1 protein containing the Bub1 kinase domain induces delocalized H2ApT120 phosphorylation, resulting in the reduction of centromeric hSgo2 and chromosome segregation errors. Collectively, these results argue that the spatial separation of kinase and phosphatase activities within the Bub complex is required for balancing its functions in the checkpoint and chromosome alignment.展开更多
During mitosis,the allocation of genetic material concurs with organelle transformation and distribution.The coordination of genetic material inheritance with organelle dynamics directs accurate mitotic progression,ce...During mitosis,the allocation of genetic material concurs with organelle transformation and distribution.The coordination of genetic material inheritance with organelle dynamics directs accurate mitotic progression,cell fate determination,and organismal homeostasis.Small GTPases belonging to the Ras superfamily regulate various cell organelles during division.Being the key regulators of membrane dynamics,the dysregulation of small GTPases is widely associated with cell organelle disruption in neoplastic and non-neoplastic diseases,such as cancer and Alzheimer’s disease.Recent discoveries shed light on the molecular properties of small GTPases as sophisticated modulators of a remarkably complex and perfect adaptors for rapid structure reformation.This review collects current knowledge on small GTPases in the regulation of cell organelles during mitosis and highlights the mediator role of small GTPase in transducing cell cycle signaling to organelle dynamics during mitosis.展开更多
In this paper,we discuss a simplified model of mitosis in frog eggs proposed by M.T. Borisuk and J.J. Tyson in [1]. By using rigorous qualitative analysis, we prove the existence of the periodic solutions on a large s...In this paper,we discuss a simplified model of mitosis in frog eggs proposed by M.T. Borisuk and J.J. Tyson in [1]. By using rigorous qualitative analysis, we prove the existence of the periodic solutions on a large scale and present the space region of the periodic solutions and the parameter region coresponding to the periodic solution. We also present the space region and the parameter region where there are no periodic solutions. The results are in accordance with the numerical results in [1] up to the qualitative property.展开更多
The present comparative review discusses conservation of early evolutionary, relic genetics in the genome of man, which determine two different mechanistic reductive division systems expressed by normal, human diploid...The present comparative review discusses conservation of early evolutionary, relic genetics in the genome of man, which determine two different mechanistic reductive division systems expressed by normal, human diploid cells. The divisions were orderly and segregated genomes reductively to near-diploid daughter cells, which showed gain of a proliferative advantage (GPA) over cells of origin. This fact of GPA expression is a fundamental requirement for initiation of tumorigenesis. The division systems were responses to a carcinogen-free induction system, consisting of short (1 - 3 days) exposures of young cells to nutritional deprivation of amino acid glutamine (AAD). In recovery growth (2 - 4 days) endo-tetra/ochtoploid cells and normal diploid metaphase cells demonstrated chromosomal reductive divisions to respectively heterozygous and homozygous altered daughter cells. Both division systems showed co-segregating whole complements, which for reduction of the diploid metaphases could only arise from gonomeric-based autonomous behavior of maternal and paternal (mat/pat) genomes. The timely associated appearance with these latter divisions was fast growing small-cells (1/2 volume-size reduced from normal diploidy), which became homozygous from haploid, genomic doubling. Both reductive divisions thus produced genome altered progeny cells with GPA, which was associated with pre-cancer-like cell-phenotypic changes. Since both “undesirable” reductive divisions expressed orderly division sequences, their genetic controls were assumed to be “old genetics”, evolutionarily conserved in the genome of man. Support for this idea was a search for evidential material in the evolutionary record from primeval time, when haploid organisms were established. The theory was that endopolyploid and gonomery-based reductive divisions relieved the early eukaryotic organisms from accidental, non-proliferative diploidy and polyploidy, bringing the organism back to vegetative haploid proliferation. Asexual cycles were common for maintenance of propagating haploid and diploid early unicellular eukaryotes. Reduction of accidental diploidy was referred to as “one-step meiosis” which meant gonomeric-based maternal and paternal genomic independent segregations. This interpretation was supported by exceptional chromosomal behaviors. However, multiple divisions expressing non-disjunction was the choice-explanation from evolutionists, which today is also suggested for the rarer LL-1 near haploid leukemia. These preserved non-mitotic mechanistic divisions systems are today witnessed in apomixes and parthenogenesis in many animal phyla. Thus, the indications are the modern genome of man harbors, relic-genetics from past “good” evolvements assuring “stable” proliferation of ancient, primitive eukaryotes, but with cancer-like effects for normal human cells.展开更多
The effects of different concentrations of manganous sulphate on root growth,cell division, chromosome and nucleus morphplogy and nucleoli in root tip-cells of Allium cepa L. were studied. The concentrations of mangan...The effects of different concentrations of manganous sulphate on root growth,cell division, chromosome and nucleus morphplogy and nucleoli in root tip-cells of Allium cepa L. were studied. The concentrations of manganous sulphate used were 10-7,10-6,10-5 ,10-4,10-3, 10-2 and 10-1mol/L. The results indicated that manganese had a stimulatory effect on the root growth at lower concentrations (10-7 to 10-4mol/L). With increasing the concentration of Mn (10-3 to 10-1mol/L) and duration of treatment,manganese inhibited root growth and cell division, and had toxic effects on chromosomes,nuclei and nucleoli. Manganese Could induce mitotic irregularities,comprising c-mitosis,anaphase bridges and chromosome stickiness. The nuclei became irregular in shape and many micronuclei were scattered in the cytoplasm. Some similar silver-stained particulate materials were found scattered in the nucleus in root tip cells. The possible mechanism behind these phenomena is also briefly discussed.展开更多
基金supported by the Science and Technology Research Project of Gansu Province[20JR5RA555 and145RTSA012]the Natural Science Foundation of Shaanxi Province[2020JQ-541]+1 种基金the National Natural Science Foundation of China[31870851 and 12175289]the Youth Innovation Promotion Association CAS[2021415]
文摘Objective To investigate the fate and underlying mechanisms of G2 phase arrest in cancer cells elicited by ionizing radiation(IR).Methods Human melanoma A375 and 92-1 cells were treated with X-rays radiation or Aurora A inhibitor MLN8237(MLN)and/or p21 depletion by small interfering RNA(si RNA).Cell cycle distribution was determined using flow cytometry and a fluorescent ubiquitin-based cell cycle indicator(FUCCI)system combined with histone H3 phosphorylation at Ser10(p S10 H3)detection.Senescence was assessed using senescence-associated-β-galactosidase(SA-β-Gal),Ki67,andγH2AX staining.Protein expression levels were determined using western blotting.Results Tumor cells suffered severe DNA damage and underwent G2 arrest after IR treatment.The damaged cells did not successfully enter M phase nor were they stably blocked at G2 phase but underwent mitotic skipping and entered G1 phase as tetraploid cells,ultimately leading to senescence in G1.During this process,the p53/p21 pathway is hyperactivated.Accompanying p21 accumulation,Aurora A kinase levels declined sharply.MLN treatment confirmed that Aurora A kinase activity is essential for mitosis skipping and senescence induction.Conclusion Persistent p21 activation during IR-induced G2 phase blockade drives Aurora A kinase degradation,leading to senescence via mitotic skipping.
基金This work was supported by the National Key Research and Development Program of China(Grant No:2021YFE0203100)National Natural Science Foundation of China(Grant Nos:81873089,81603253 and 81973570)+1 种基金Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No:ZYYCXTD-C-202009)Innovation Team and Talents Cultivation Program ofNational Administration ofTraditional Chinese Medicine(Grant No:ZYYCXTD-D-202002).
文摘Cancer has been an insurmountable problem in the history of medical science.The uncontrollable proliferation of cancer cells is one of cancers main characteristics,which is closely associated with abn ormal mitosis.Targeting mitosis is an effective method for cancer treatment.This review summarizes several natural products with anti-tumor effects related to mitosis,focusing on targeting microtubulin,inducing DNA damage,and modulating mitosis-associated kinases.Furthermore,the main disadvantages of several typical compounds,including drug resistance,toxicity to non-tumor tissues,and poor aqueous solubility and pharmacokinetic properties,are also discussed,together with strategies to address them.Improved understanding of cancer cell mitosis and natural products may pave the way to drug development for the treatment of cancer.
文摘BACKGROUND Mammary-type myofibroblastoma(MTMF)is a rare benign extramammary soft tissue tumor with myofibroblastic differentiation.Although 160 cases of MTMF have been reported in the literature since 2001,no cases of infarction or atypical mitosis have been reported so far.Herein,we report an unusual case of MTMF in the pelvic cavity,which mimicked some malignant features,including infarction,atypical mitosis,infiltrative growth,and prominent cytologic atypia,making it difficult to ascertain whether the tumor was benign.CASE SUMMARY A 49-year-old man complained of pain and discomfort in the right buttock for more than 4 mo and did not receive any treatment.Nuclear magnetic resonance imaging(MRI)showed a 13-cm-sized mass in his right pelvic cavity.Histologically significant differences were atypical mitosis figures and multiple necrotic foci in the tumor.In addition,smooth muscle and skeletal muscle were invaded within and at the edge of the tumor.These morphologic features are often reminiscent of malignant tumors and therefore pose a diagnostic challenge to pathologists.The tumor cells were strongly positive for both cluster of differentiation 34 and desmin,and the loss of retinoblastoma 1 shown by immunohistochemical and fluorescence in situ hybridization results confirmed the pathological diagnosis of MTMF.Currently,the patient is alive and in good condition without tumor recurrence or metastasis after 2.5 years of follow-up by telephone and MRI.CONCLUSION The two pseudo-malignant characteristics of infarction and atypical mitosis broaden the morphological lineage of MTMF,a rare mesenchymal tumor.
文摘Tetraploid induction was carried out by inhibiting mitosis I in fertilized eggs of Chlamys farreri . Mitosis I was blocked with cold shock (5 7℃), Cytochalasin B (0.75 mg/L) and 6 dimethylaminopurine (6 DMAP) (60 75 mg/L) when 60% fertilized eggs released polar body II at 20℃. At 4 cells embryo stage, the ploidy was determined by counting chromosome number. In control groups, most embryos were diploids (72.22%) and aneuploids (24.78%). In Cytochalasin B, cold shock and 6 DMAP treated groups, tetraploids were respectively 10.51%, 4.08%, and 13.34%; aneuploids were 43.10%, 35.93% and 29.16%,and triploids were 7.84%, 8.52% and 18.33%. At D larva stage, ploidy was determined by flow cytometry (FCM). The ploidy analysis of day 2 larvae showed diploids in control group and also in three treated groups. Juvenile scallops (0.2 0.3cm) which were harvested in two control groups and two CB treated groups were all diploids through checking ploidy individually by FCM.
文摘The modified approach to conventional Artificial Neural Networks (ANN) described in this paper represents an essential departure from the conventional techniques of structural analysis. It has four main distinguishing features: 1) it introduces a new simulation algorithm based on the biology;2) it performs relatively simple arithmetic as massively parallel, during analysis of a structure;3) it shows that it is possible to use the application of the modified approach to conventional ANN to solve problems of any complexity in the field of structural analysis;4) the Neural Topologies for Structural Analysis (NTSA) system are recurrent networks and its outputs are connected to its inputs [1] and [2]. In NTSA system the DNA of the neuron mother and daughters would be defined by: 1) the same entry, from the corresponding neuron in the previous layer;2) the same trend vector;3) the same transfer function (purelin). The mother’s neuron and her daughter’s neuron differ only in the connection weight and its output signal.
文摘Background:Cell division is one of the key roles in the cell development,cell differentiation,embryogenesis and recovery of tissues.Independent studies have shown that spindle alignment during not only asymmetric but also symmetric cell divisions is essential
基金Fundação de AmparoàPesquisa do Estado São Paulo(FAPESP,São Paulo,Brazil)through Grant Temático,No.2017/03489-1.
文摘BACKGROUND Tubulins,building blocks of microtubules,are modified substrates of diverse post-translational modifications including phosphorylation,polyglycylation and polyglutamylation.Polyglutamylation of microtubules,catalyzed by enzymes from the tubulin tyrosine ligase-like(TTLL)family,can regulate interactions with molecular motors and other proteins.Due to the diversity and functional importance of microtubule modifications,strict control of the TTLL enzymes has been suggested.AIM To characterize the interaction between never in mitosis gene A-related kinase 5(NEK5)and TTLL4 proteins and the effects of TTLL4 phosphorylation.METHODS The interaction between NEK5 and TTLL4 was identified by yeast two-hybrid screening using the C-terminus of NEK5(a.a.260–708)as bait and confirmed by immunoprecipitation.The phosphorylation sites of TTLL4 were identified by mass spectrometry and point mutations were introduced.RESULTS Here,we show that NEK5 interacts with TTLL4 and regulates its polyglutamylation activity.We further show that NEK5 can also interact with TTLL5 and TTLL7.The silencing of NEK5 increases the levels of polyglutamylation of proteins by increasing the activity of TTLL4.The same effects were observed after the expression of the catalytically inactive form of NEK5.This regulation of TTLL4 activity involves its phosphorylation at Y815 and S1136 amino acid residues.CONCLUSION Our results demonstrate,for the first time,the regulation of TTLL activity through phosphorylation,pointing to NEK5 as a potential effector kinase.We also suggest a general control of tubulin polyglutamylation through NEK family members in human cells.
文摘The effects of growth factors and calcium concentrations present in different culture media on induction of terminal differentiation were investigated for four different epidermoid carcinoma cell lines, Hela, KB, A431, and SCC-25, and their responses determined relative to those elicited by normal human keratinocytes subjected to these culture conditions. Differentiation status was determined cyto-chemically by a validated keratin protein staining method, and by autoradiographic analyses. Growth and differentiation promoting factors that influenced the direction of integrated control of growth and differentiation in normal human keratinocytes were found to be effective for some cell lines but not others. The factors examined were 1) high density arrest in serum-free and serum-containing media, 2) media shifts from high density culture in serum-containing media to low density growth factor-depleted or supplemented serum-free medium, and 3) the concentration of calcium in the media. The extent and degree of differentiation achieved varied among different cell lines depend on the presence or absence of serum, EGF and insulin protein growth factors. Certain growth media appear to sponsor keratin protein, cyto-chemically-detected differentiation, and evidence of quantal mitotic division in low density HeLa cell and SCC25 cell cultures. Epidermoid carcinoma cell lines retain limited capacity to commit to early stages of cell differentiation.
文摘To explore the clinicopathological features of abound mitosis of the hepatocytes in intrahepatic cholelithiasis.The clinicopathological data of one case diagnosed as intrahepatic cholelithiasis was collected from Yantai Yuhuangding Hospital and the clinicopathological characters were discussed.A 68-year-old man suffered from the pain in the right upper quadrant and radiology showed multiple stones in the gallbladder and left liver.The images suggested intrahepatic cholelithiasis.The patient received gallbladder and partial hepatectomy.A large number of mitosis was observed and twelve nuclear fissions were found under high magnification,even in some area pathological nuclear fission could be observed in morphology.On the basis of detection in laboratory,the diagnosis of intrahepatic cholelithiasis was made.The patient did not receive any therapy after surgery.The patient was in a good condition after 18 months follow-up.Increased number of hepatic mitosis might be due to the stimulation from stones,hepatic biliary or secondary inflammatory.High index of proliferation should be prevented from the potential misdiagnosis of hepatic tumor.
基金supported by grants from the Ministry of Science and Technology of the People’s Republic of China and the National Natural Science Foundation of China(2022YFA1303100,2022YFA0806800,92153302,32090040,92254302,21922706,91853115 to X.L.,2017YFA0503600,31621002,U1532109,91853133 to J.Z.,32170733,2017YFA0102900,31871359 to Z.D.,32000858 to T.T.)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB37010105 to J.Z.and XDB19040000 to X.L.)+3 种基金the Ministry of Education(IRT_17R102,20113402130010,YD2070006001 to X.L.)Anhui Provincial Natural Science Foundation(2108085J15 to Z.D.,2008085QC145 to T.T.)the Fundamental Research Funds for the Central Universities(WK2070000171 to T.T.)the University of Science and Technology of China Research Funds of the Double First-Class Initiative(YD2070002015 to X.Z.)。
文摘In mitosis,accurate chromosome segregation depends on the kinetochore,a supermolecular machinery that couples dynamic spin-dle microtubules to centromeric chromatin.However,the structure–activity relationship of the constitutive centromere-associated network(CCAN)during mitosis remains uncharacterized.Building on our recent cryo-electron microscopic analyses of human CCAN structure,we investigated how dynamic phosphorylation of human CENP-N regulates accurate chromosome segregation.Our mass spectrometric analyses revealed mitotic phosphorylation of CENP-N by CDK1,which modulates the CENP-L–CENP-N interaction for accurate chromosome segregation and CCAN organization.Perturbation of CENP-N phosphorylation is shown to prevent proper chromosome alignment and activate the spindle assembly checkpoint.These analyses provide mechanistic insight into a previously undefined link between the centromere–kinetochore network and accurate chromosome segregation.
文摘In this paper,the biological function of PLK-1,the correlation between PLK-1 and tumors,and the latest research progress on PLK-1 inhibitors under study are reviewed,in order to provide references for the research and development of PLK-1 inhibitors.
基金grants from the Ministry of Science and Technology of the People's Republic of China (2017YFA0503600 and 2016YFA0100500)the National Natural Science Foundation of China (31430054,31320103904, 91313303,31621002,31501095,and 31671405)+1 种基金the Ministry of Education of the People's Republic of China (IRT_17R102)the US National Institutes of Health (CA164133,DK56292, and DKl15812).
文摘Heterochromatin protein 1α (HP1α)regulates chromatin specification and plasticity during cell fate decision.Different structural determinants account for HP1α Localization and function during cell division cycle.Our earlier study showed that centromeric Localization of HP1α depends on the epigenetic mark H3K9me3 in interphase,while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors.Here,we identified a PXVXL-containing protein,Ligand-dependent nuclear receptorinteracting factor 1 (LRIF1),which recruits HPla to the centromere of mitotic chromosomes and its interaction with HP1α is essential for accurate chromosome segregation during mitosis.LRIF1 interacts directly with HPla chromoshadow domain via an evolutionariLy conserved PXVXL motif within its C-terminus.Importantly,the LRIF1-HPla interaction is critical for Aurora B activity in the inner centromere.Mutation of PXVXL motif of LRIF1 Leads to defects in HPla centromere targeting and aberrant chromosome segregation.These findings reveal a previously unrecognized direct Link between LRIF1 and HP1α in centromere plasticity control and illustrate the critical role of LRIF1-HP1α interaction in orchestrating accurate cell division.
文摘As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.
基金the National Natural Science Foundation of China.
文摘The nuclear lamina is a meshwork of intermediate filament-like fibrils situated immediately subjacent to the inner membrane of the nuclear envelope. Together with other proteinaceous elements such as the nuclear pore complex, the lamina forms part of the karyoskeleton, or structural framework of the nucleus. The lamina is thought to play a role in anchoring the nuclear envelope, and/or providing attachment sites for interphase chromatin. Mammalian somatic cells commonly contain three major lamins: A, B and C.
基金supported by grants from the National Key Re-search and Development Program of China(2017YFA0503600 and 2016YFA0100500)the National Natural Science Founda-tion of China(31621002,32090040,91854203,21922706,91853115,92153302,22177106,92053104,31970655,and 32100612)+2 种基金the Ministry of Education(IRT_17R102),Anhui Provincial Natural Science Foundation(2108085J15)the Strate-gic Priority Research Program of the Chinese Academy of Sci-ences(XDB19040000)the Fundamental Research Funds for the Central Universities(WK2070000066 and WK2070000194).
文摘Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation.In eukaryotic cells,nuclear envelope breakdown(NEBD)is required for proper chromosome segregation.Although a list of mitotic kinases has been implicated in NEBD,how they coordinate their activity to dissolve the nuclear envelope and protein machinery such as nuclear pore complexes was unclear.Here,we identified a regulatory mechanism in which Nup62 is acetylated by TIP60 in human cell division.Nup62 is a novel substrate of TIP60,and the acetylation of Lys432 by TIP60 dissolves nucleoporin Nup62-Nup58-Nup54 complex during entry into mitosis.Importantly,this acetylation-elicited remodeling of nucleoporin complex promotes the distribution of Nup62 to the mitotic spindle,which is indispensable for orchestrating correct spindle orientation.Moreover,suppression of Nup62 perturbs accurate chromosome segregation during mitosis.These results establish a previously uncharacterized regulatory mechanism in which TIP60-elicited nucleoporin dynamics promotes chromosome segregation in mitosis.
基金supported by the National Natural Science Foundation of China(31970666)Taishan Scholar Project(tsqn201812054)from Shandong,China+3 种基金Work at the Novo Nordisk Foundation Center for Protein Research was supported by the grant NNF14CC0001J.N.is supported by grants from the Danish Cancer Society(R269-A15586-B17)Independent Research Fund Denmark(8021-00101B and 0134-00199B)Novo Nordisk Foundation(NNF20OC0065098).
文摘The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogs with Bub1 being a kinase, while BubR1 localizes the PP2A-B56 protein phosphatase to kinetochores in humans. Whether this spatial separation of kinase and phosphatase activity is important is unclear as some organisms integrate both activities into one Bub protein. Here, we engineer human Bub1 and BubR1 proteins integrating kinase and phosphatase activities into one protein and show that these do not support normal mitotic progression. A Bub1–PP2A-B56 complex can support chromosome alignment but results in impairment of the checkpoint due to dephosphorylation of the Mad1 binding site in Bub1. Furthermore, a chimeric BubR1 protein containing the Bub1 kinase domain induces delocalized H2ApT120 phosphorylation, resulting in the reduction of centromeric hSgo2 and chromosome segregation errors. Collectively, these results argue that the spatial separation of kinase and phosphatase activities within the Bub complex is required for balancing its functions in the checkpoint and chromosome alignment.
基金supported by the National Kcy R&D Program of China(Nos.2019YFA0110300 and 2017YFA0505600-04)the National Natural Science Foundation of China(Nos.81820108024 and 81630005)+1 种基金the Innovative Research Team in University of Ministry of Edueation of China(No.IRT-17R15)and the Natural Science Foundation of Guangdong(Nos.2016A030311038 and 2017A030313608).
文摘During mitosis,the allocation of genetic material concurs with organelle transformation and distribution.The coordination of genetic material inheritance with organelle dynamics directs accurate mitotic progression,cell fate determination,and organismal homeostasis.Small GTPases belonging to the Ras superfamily regulate various cell organelles during division.Being the key regulators of membrane dynamics,the dysregulation of small GTPases is widely associated with cell organelle disruption in neoplastic and non-neoplastic diseases,such as cancer and Alzheimer’s disease.Recent discoveries shed light on the molecular properties of small GTPases as sophisticated modulators of a remarkably complex and perfect adaptors for rapid structure reformation.This review collects current knowledge on small GTPases in the regulation of cell organelles during mitosis and highlights the mediator role of small GTPase in transducing cell cycle signaling to organelle dynamics during mitosis.
基金the the National Natural Science Foundation of China (No.10171099).
文摘In this paper,we discuss a simplified model of mitosis in frog eggs proposed by M.T. Borisuk and J.J. Tyson in [1]. By using rigorous qualitative analysis, we prove the existence of the periodic solutions on a large scale and present the space region of the periodic solutions and the parameter region coresponding to the periodic solution. We also present the space region and the parameter region where there are no periodic solutions. The results are in accordance with the numerical results in [1] up to the qualitative property.
文摘The present comparative review discusses conservation of early evolutionary, relic genetics in the genome of man, which determine two different mechanistic reductive division systems expressed by normal, human diploid cells. The divisions were orderly and segregated genomes reductively to near-diploid daughter cells, which showed gain of a proliferative advantage (GPA) over cells of origin. This fact of GPA expression is a fundamental requirement for initiation of tumorigenesis. The division systems were responses to a carcinogen-free induction system, consisting of short (1 - 3 days) exposures of young cells to nutritional deprivation of amino acid glutamine (AAD). In recovery growth (2 - 4 days) endo-tetra/ochtoploid cells and normal diploid metaphase cells demonstrated chromosomal reductive divisions to respectively heterozygous and homozygous altered daughter cells. Both division systems showed co-segregating whole complements, which for reduction of the diploid metaphases could only arise from gonomeric-based autonomous behavior of maternal and paternal (mat/pat) genomes. The timely associated appearance with these latter divisions was fast growing small-cells (1/2 volume-size reduced from normal diploidy), which became homozygous from haploid, genomic doubling. Both reductive divisions thus produced genome altered progeny cells with GPA, which was associated with pre-cancer-like cell-phenotypic changes. Since both “undesirable” reductive divisions expressed orderly division sequences, their genetic controls were assumed to be “old genetics”, evolutionarily conserved in the genome of man. Support for this idea was a search for evidential material in the evolutionary record from primeval time, when haploid organisms were established. The theory was that endopolyploid and gonomery-based reductive divisions relieved the early eukaryotic organisms from accidental, non-proliferative diploidy and polyploidy, bringing the organism back to vegetative haploid proliferation. Asexual cycles were common for maintenance of propagating haploid and diploid early unicellular eukaryotes. Reduction of accidental diploidy was referred to as “one-step meiosis” which meant gonomeric-based maternal and paternal genomic independent segregations. This interpretation was supported by exceptional chromosomal behaviors. However, multiple divisions expressing non-disjunction was the choice-explanation from evolutionists, which today is also suggested for the rarer LL-1 near haploid leukemia. These preserved non-mitotic mechanistic divisions systems are today witnessed in apomixes and parthenogenesis in many animal phyla. Thus, the indications are the modern genome of man harbors, relic-genetics from past “good” evolvements assuring “stable” proliferation of ancient, primitive eukaryotes, but with cancer-like effects for normal human cells.
文摘The effects of different concentrations of manganous sulphate on root growth,cell division, chromosome and nucleus morphplogy and nucleoli in root tip-cells of Allium cepa L. were studied. The concentrations of manganous sulphate used were 10-7,10-6,10-5 ,10-4,10-3, 10-2 and 10-1mol/L. The results indicated that manganese had a stimulatory effect on the root growth at lower concentrations (10-7 to 10-4mol/L). With increasing the concentration of Mn (10-3 to 10-1mol/L) and duration of treatment,manganese inhibited root growth and cell division, and had toxic effects on chromosomes,nuclei and nucleoli. Manganese Could induce mitotic irregularities,comprising c-mitosis,anaphase bridges and chromosome stickiness. The nuclei became irregular in shape and many micronuclei were scattered in the cytoplasm. Some similar silver-stained particulate materials were found scattered in the nucleus in root tip cells. The possible mechanism behind these phenomena is also briefly discussed.
