2014 Vol. 5, No. 6

Surpassing the advanced comes from continuous accumulation
Baoyuan Zhang, Jing Qu, Nur Estya Binte Rahman
2014, 5(6): 409-410. doi: 10.1007/s13238-014-0056-x
DNA replication components as regulators of epigenetic inheritance—lesson from fission yeast centromere
Haijin He, Marlyn Gonzalez, Fan Zhang, Fei Li
2014, 5(6): 411-419. doi: 10.1007/s13238-014-0049-9
Genetic information stored in DNA is accurately copied and transferred to subsequent generations through DNA replication. This process is accomplished through the concerted actions of highly conserved DNA replication components. Epigenetic information stored in the form of histone modifications and DNA methylation, constitutes a second layer of regulatory information important for many cellular processes, such as gene expression regulation, chromatin organization, and genome stability. During DNA replication, epigenetic information must also be faithfully transmitted to subsequent generations. How this monumental task is achieved remains poorly understood. In this review, we will discuss recent advances on the role of DNA replication components in the inheritance of epigenetic marks, with a particular focus on epigenetic regulation in fission yeast. Based on these findings, we propose that specific DNA replication components function as key regulators in the replication of epigenetic information across the genome.
Intercellular protein-protein interactions at synapses
Xiaofei Yang, Dongmei Hou, Wei Jiang, Chen Zhang
2014, 5(6): 420-444. doi: 10.1007/s13238-014-0054-z
Chemical synapses are asymmetric intercellular junctions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules (CAMs) at synaptic clefts. The CAM proteins link pre-and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion channels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer's disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.
Research articles
Impaired tumor angiogenesis and VEGFinduced pathway in endothelial CD146 knockout mice
Qiqun Zeng, Zhenzhen Wu, Hongxia Duan, Xuan Jiang, Tao Tu, Di Lu, Yongting Luo, Ping Wang, Lina Song, Jing Feng, Dongling Yang, Xiyun Yan
2014, 5(6): 445-456. doi: 10.1007/s13238-014-0047-y
CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angiogenic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout (CD146EC-KO) mice using the Tg(Tek-cre) system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146EC-KO mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells (ECs) ofCD146EC-KO mice. Mechanistic studies further confirmed that VEGFinduced VEGFR-2 phosphorylation and AKT/p38 MAPKs/NF-κB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146EC-KO mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis.
Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy
Jiangmei Li, Lunfeng Zhang, Zhen Gao, Hua Kang, Guohua Rong, Xu Zhang, Chang Chen
2014, 5(6): 457-468. doi: 10.1007/s13238-014-0055-y
Our previous studies indicate that phosphatidylinositol 4-kinase Ⅱα can promote the growth of multi-malignant tumors via HER-2/PI3K and MAPK pathways. However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KⅡα could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KⅡα knockdown reduced EGFR protein level, and the expression of PI4KⅡα shows a strong correlation with EGFR in human breast cancer tissues (r=0.77, P < 0.01). PI4KⅡα knockdown greatly prolonged the effects and decreased the effective dosage of AG-1478, a specific inhibitor of EGFR. In addition, it significantly enhanced AG1478-induced inhibition of tumor cell survival and strengthened the effect of the EGFR-targeting anti-cancer drug Iressa in xenograft tumor models. Mechanistically, we found that PI4KⅡα suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture (SILAC) and LC-MS/MS suggested that HSP90 mediated the effect of PI4KⅡα on EGFR. Furthermore, we found that combined inhibition of PI4KⅡα and EGFR suppressed both PI3K/AKT and MAPK/ERK pathways, and resulted in downregulation of multiple oncogenes like PRDX2, FASN, MTA2, ultimately leading to suppression of tumor growth. Therefore, we conclude that combined inhibition of PI4KⅡα and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KⅡα presents a novel strategyto combat EGFR-dependent tumors.
End-binding protein 1 stimulates paclitaxel sensitivity in breast cancer by promoting its actions toward microtubule assembly and stability
Youguang Luo, Dengwen Li, Jie Ran, Bing Yan, Jie Chen, Xin Dong, Zhu Liu, Ruming Liu, Jun Zhou, Min Liu
2014, 5(6): 469-479. doi: 10.1007/s13238-014-0053-0
Paclitaxel is a microtubule-targeting agent widely used for the treatment of many solid tumors. However, patients show variable sensitivity to this drug, and effective diagnostic tests predicting drug sensitivity remain to be investigated. Herein, we show that the expression of end-binding protein 1 (EB1), a regulator of microtubule dynamics involved in multiple cellular activities, in breast tumor tissues correlates with the pathological response of tumors to paclitaxel-based chemotherapy. In vitro cell proliferation assays reveal that EB1 stimulates paclitaxel sensitivity in breast cancer cell lines. Our data further demonstrate that EB1 increases the activity of paclitaxel to cause mitotic arrest and apoptosis in cancer cells. In addition, microtubule binding affinity analysis and polymerization/depolymerization assays show that EB1 enhances paclitaxel binding to microtubules and stimulates the ability of paclitaxel to promote microtubule assembly and stabilization. These findings thus reveal EB1 as a critical regulator of paclitaxel sensitivity and have important implications in breast cancer chemotherapy.
Coevolution signals capture the specific packing of secondary structures in protein architecture
Lizong Deng, Xiaoxi Dong, Aiping Wu, Tingrui Song, Taijiao Jiang
2014, 5(6): 480-483. doi: 10.1007/s13238-014-0051-2
Autofluorescence of MDA-modified proteins as an in vitro and in vivo probe in oxidative stress analysis
Min Qiang, Yajie Xu, Yang Lu, Yingge He, Chanshuai Han, Ying Liu, Rongqiao He
2014, 5(6): 484-487. doi: 10.1007/s13238-014-0052-1