Distinct Cytoskeletal Injuries Induced by As,Cd,Co,Cr,and Ni Compounds

The risks of metal compounds to human health are highlighted by the ubiquity of exposure and their persistence in the environment.Although compounds of As,Cd,Co,Cr,and Ni are known or“reasonably anticipated”to be carcinogenic to humans and/or experimental animals, the cellular targets of these health hazards and the underlying mechanisms of their carcinogenic- ity are still unclear.We show in this report that dramatic,time-and dose-dependent cytoskeletal perturbations,especially in the distribution and organization patterns of microtubules and mi- crofilaments,two of the principal components of the cytoskeleton,occurred in 3T3 cells upon exposure to these metal salts.Each metal salt appeared to induce a different,typical pattern of cytoskeletal injury,probably reflecting the specificity of action of each metal ion.These results suggest that the cytoskeleton can indeed act as a target for injury by epigenetic carcinogenic metal compounds in the environment.These findings should help our efforts to understand the mechanisms of action of metal compounds at the subcellular and molecular levels.1989 Academic Press,Inc.

Tumor-and osteoclast-derived NRP2 in prostate cancer bone metastases

Understanding the role of neuropilin 2(NRP2)in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis.We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone.Here,we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis,implicating NRP2 as a promising therapeutic target.Since,osteoclasts present in the tumor microenvironment express NRP2,we have investigated the potential effect of targeting NRP2 in osteoclasts.Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions.Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function.Interestingly,depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone.These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

Insulin exerts direct, IGF-1 independent actions in growth plate chondrocytes

Insufficient insulin production or action in diabetic states is associated with growth retardation and impaired bone healing, while the underling mechanisms are unknown. In this study, we sought to define the role of insulin signaling in the growth plate. Insulin treatment of embryonic metatarsal bones from wild-type mice increased chondrocyte proliferation. Mice lacking insulin receptor （IR） selectively in chondrocytes （CartIR-/-） had no discernable differences in total femoral length compared to control littermates. However, CartIR-/- mice exhibited an increase in chondrocyte numbers in the growth plate than that of the controls. Chondrocytes lacking IR had elevated insulin-like growth factor （IGF）-IR mRNA and protein levels. Subsequently, IGF-1 induced phosphorylafion of Akt and ERK was enhanced, while this action was eliminated when the cells were treated with IGF-1R inhibitor Picropodophyllin. Deletion of the IR impaired chondrogenic differentiation, and the effect could not be restored by treatment of insulin, but partially rescued by IGF-1 treatment. Intriguingly, the size of hypertrophic chondrocytes was smaller in CartIR-/- mice when compared with that of the control littermates, which was associated with upregnlation of tuberous sclerosis complex 2 （TSC2）. These results suggest that deletion of the IR in chondrocytes sensitizes IGF-1R signaling and action, IR and IGF-1R coordinate to regulate the proliferation, differentiation and hypertrophy of growth plate chondrocytes.

Enhanced apoptosis during early neuronal differentiation in mouse ES cells with autosomal imbalance

尽管特别 chromosomal 症候群是 phenotypically 并且临床上不同的，有正染色体的不平衡的个人的多数例如 aneuploidy，表明智力迟钝。普通反常显型在症候群(DS ) 下面，最流行的正染色体的 aneuploidy，在大脑在数字和神经原的密度显示出减小。作为一个 DS 模型，我们最近从包含一个单个人的染色体的 ES 房间创造了妄想的老鼠 21。老鼠模仿了 DS 的典型 phenotypic 特征，并且 ES 房间在 vitro 在早 neuronal 区别期间显示出 apoptosis 的更高的发生。在这研究，我们由转移各种各样的人的染色体或另外的鼠标染色体在鼠标 ES 房间由 aneuploidy 检验了异常早神经的开发的正式就职。结果在在 vitro 在早 neuronal 区别期间检验的所有 autosome-aneuploid 克隆显示出 apoptosis 的提高的发生。进一步， cDNA microarray 分析揭示了下面调整的基因，八已知的基因与房间增长，神经突长出和区别有关是的普通的簇。重要地，由在正常老鼠 ES 房间击倒的 siRNA 这些基因指向在早 neuronal 区别期间导致了提高的 apoptosis。这些调查结果强烈建议那正染色体的不平衡为 apoptosis 通过普通分子的机制与一般 neuronal 损失被联系。