p53 and DNA-dependent protein kinase catalytic subunit independently function in regulating actin damage-induced tetraploid G1 arrest

We previously reported that the p53 tumor suppressor protein plays an essential role in the induction of tetraploid G1 arrest in response to perturbation of the actin cytoskeleton, termed actin damage. In this study, we investigated the role of p53, ataxia telangiectasia mutated protein (ATM), and catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in tetraploid G1 arrest induced by actin damage. Treatment with actin- damaging agents including pectenotoxin-2 (PTX-2) increases phosphorylation of Ser-15 and Ser-37 residues of p53, but not Ser-20 residue. Knockdown of ATM and DNA-PKcs do not affect p53 phosphorylation induced by actin damage. However, while ATM knockdown does not affect tetraploid G1 arrest, knockdown of DNA-PKcs not only perturbs tetraploid G1 arrest, but also results in formation of polyploidy and induction of apoptosis. These results indicate that DNA-PKcs is essential for the maintenance of actin damage induced- tetraploid G1 arrest in a p53-independent manner. Furthermore, actin damage-induced p53 expression is not observed in cells synchronized at G1/S of the cell cycle, implying that p53 induction is due to actin damage-induced tetraploidy rather than perturbation of actin cytoskeleton. Therefore, these results suggest that p53 and DNA- PKcs independently function for tetraploid G1 arrest and preventing polyploidy formation.     

Physical mechanism of the compressive response of F-actin networks: significance of crosslinker unbinding events

A model of crosslinker unbinding is implemented in a highly coarse-grained granular model of F-actin cytoskeleton. We employ this specific granular model to study the mechanisms of the compressive responses of F-actin networks. It is found that the compressive response of F-actin cytoskeleton has dependency on the strain rate. The evolution of deformation energy in the network indicates that crosslinker unbinding events can induce the remodelling of F-actin cytoskeleton in response to external loadings. The internal stress in F-actin cytoskeleton can efficiently dissipate with the help of crosslinker unbinding, which could lead to the spontaneous relaxation of living cells.     

基于信号分子双向输运的运动细胞极性反转模拟

为解释运动细胞极性反转实验所发生的现象, 依据调控细胞极化的信号级联转导关系, 构建了包含一对非稳态二维反应—扩散方程的数学模型, 并采用格子Boltzmann 方法数值求解. 数值实验显示, 当反向信号使胞内Rac 的活化梯度值达到和超过初始正向极化梯度的1.5 倍时, 负责细胞极化的Rac-PIs 反馈回路产生时空调控效应, 可驱动伪足标识信号分子(如磷酸激酶(PI3K) 和磷脂酰肌醇-3, 4, 5- 三磷酸(PIP₃)) 和尾部标识信号分子(如磷酸酶(PTEN) 和磷脂酰肌醇-4, 5- 双磷酸(PIP₂)) 发生双向输运, 并最终重新积聚于对极. 模拟得到的极性反转时程曲线与已有实验吻合. 此外, 针对实验观测到的新伪足开始形成与原先伪足完全消失之间存在着延滞时间(~30 s), 该文证实这是由于细胞两极对游离态激活酶(例如, PI3K) 展开竞争所致, 无需引入前人所设想的全局性抑制因子的作用.      

Effects of polar cortical cytoskeleton and unbalanced cortical surface tension on intercellular bridge thinning during cytokinesis

To probe the contributions of polar cortical cytoskeleton and the surface tension of daughter cells to intercellular bridge thinning dynamics during cytokinesis,we applied cytochalasin D(CD) or colchicine(COLC) in a highly localized manner to polar regions of dividing normal rat kidney(NRK) cells.We observed cellular morphological changes and analyzed the intercellular bridge thinning trajectories of dividing cells with different polar cortical characteristics.Global blebbistatin(BS) application was used to obtain cells losing active contractile force groups.Our results show that locally released CD or colchicine at the polar region caused inhibition of cytokinesis before ingression.Similar treatment at phases after ingression allowed completion of cytokinesis but dramatically influenced the trajectories of intercellular bridge thinning.Disturbing single polar cortical actin induced transformation of the intercellular bridge thinning process,and polar cortical tension controlled deformation time of intercellular bridges.Our study provides a feasible framework to induce and analyze the effects of local changes in mechanical properties of cellular components on single cellular cytokinesis.     

Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic,Antiproliferative, and Antineoplastic Effects

The marine environment is highly diverse, each living creature fighting to establish and proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules’ origins and activities have been systematic, although much is still to be discovered. Their broad chemical diversity results from integrating peptide and polyketide synthetases and synthases, along with cascades of biosynthetic transformations resulting in new chemical structures. Cyanobacteria are glycolipid, macrolide, peptide, and polyketide producers, and to date, hundreds of these molecules have been isolated and tested. Many of these compounds have demonstrated important bioactivities such as cytotoxicity, antineoplastic, and antiproliferative activity with potential pharmacological uses. Some are currently under clinical investigation. Additionally, conventional chemotherapeutic treatments include drugs with a well-known range of side effects, making anticancer drug research from new sources, such as marine cyanobacteria, necessary. This review is focused on the anticancer bioactivities of metabolites produced by marine cyanobacteria, emphasizing the identification of each variant of the metabolite family, their chemical structures, and the mechanisms of action underlying their biological and pharmacological activities.     

Cytoskeleton and Chromosome Damage Leading to Abnormal Mitosis Were Involved in Multinucleated Cells Induced by Silicon Nanoparticles

Recently, amorphous silicon nanoparticles (SNPs) are widely used in a variety of fields, especially in biological and medical science. Thus, the adverse effect of these nanoparticles should be carefully investigated. The multinucleation effect of SNPs was firstly reported in our previous studies, while the relative mechanism is still unclear. Therefore, the purpose of this study is to investigate the mechanisms with regard to the formation of multinucleated cells. Two sizes of amorphous SNPs (Nano‐Si64 and Nano‐Si46) are carefully characterized. Cytotoxicity and rate of multinucleated cells are firstly determined after human hepatic L‐02 cells are treated with two SNPs for 24 h. Then cell fusion and abnormal mitosis, two ways could form multinucleated cells, are investigated, respectively. Results indicated that SNPs produce a dose‐dependent and size‐related multinucleation effect in L‐02 cells. Abnormal mitosis instead of cell fusion is the main reason for the formation of multinucleated cells caused by SNPs. Both two SNPs could affect the quantity and distribution of cytoskeleton through extra ROS and Ca²⁺ leading to abnormal mitosis and cytokinesis. Additionally, chromosome damage resulting in corresponding G2/M cell cycle arrest should be another aspect, which finally leads to the formation of multinucleated cells in L‐02 cell line.     

Involvement of ��PIX in angiotensin II-induced migration of vascular smooth muscle cells

Angiotensin II (Ang II) stimulates migration of vascular smooth muscle cell (VSMC) in addition to its contribution to contraction and hypertrophy. It is well established that Rho GTPases regulate cellular contractility and migration by reorganizing the actin cytoskeleton. Ang II activates Rac1 GTPase, but its upstream guanine nucleotide exchange factor (GEF) remains elusive. Here, we show that Ang II-induced VSMC migration occurs in a βPIX GEF-dependent manner. βPIX-specific siRNA treatment significantly inhibited Ang II-induced VSMC migration. Ang II activated the catalytic activity of βPIX towards Rac1 in dose- and time-dependent manners. Activity reached a peak at 10 min and declined close to a basal level by 30 min following stimulation. Pharmacological inhibition with specific kinase inhibitors revealed the participation of protein kinase C, Src family kinase, and phosphatidylinositol 3-kinase (PI3-K) upstream of βPIX. Both p21-activated kinase and reactive oxygen species played key roles in cytoskeletal reorganization downstream of βPIX-Rac1. Taken together, our results suggest that βPIX is involved in Ang II-induced VSMC migration.     

离子注入对黑松花粉粒和花粉管内骨架系统的损伤效应

以黑松花粉粒和花粉管为试验材料, 研究了离子注入对细胞骨架系统的损伤效应。研究结果表明, 离子注入会不同程度地破坏花粉管内微管网络的完整性, 花粉管形态的异常状态与其微管骨架结构的异常状态密切相关。离子注入对黑松花粉管内的微管骨架系统的正常结构有明显的效应, 这种效应的明显程度与离子注入剂量有一定的相关性, 即随着离子注入剂量的增加, 微管骨架系统受到破坏的程度更加明显。离子注入对黑松花粉管内微丝骨架系统的分布状态有明显的影响, 其程度也与离子注入剂量的大小存在一定的相关性。     

细胞骨架生物力学进展

细胞骨架力学作为力学细胞生物学的一个新兴领域, 其研究方法突破传统细胞力学思想, 不再把活细胞简化为皮质膜包着的弹性、黏性或黏弹性连续介质体, 而是基于在细胞变形和功能中发挥重要作用的细胞骨架离散网络结构, 在微/纳米尺度建立一种集细胞形态和功能于一体的离散网络结构. 这种细胞骨架模型作为细胞变形和生化事件调控的纽带, 能从分子层次上阐述细胞运动、能量转换、信息传递、基因表达等重大生命活动的潜在机制,同时也能解释生物大分子间相互作用、受体/配体特异性相互作用、大分子自装配、细胞及分子层次的力学-化学耦合, 为定量研究细胞-亚细胞-生物大分子等在多种力学刺激下的响应建立了良好的平台, 对于理解生物模式形成、生物复杂性以及解决重大生物学难题具有深远意义. 本文基于细胞骨架三维离散网络结构特点及其生物学背景, 从生物力学角度详细阐述近几年国际上流行的细胞骨架模型理论分析和研究成果的最新进展.