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Public Key Cryptography Standards: PKCS  [PDF]
Yongge Wang
Computer Science , 2012,
Abstract: Cryptographic standards serve two important goals: making different implementations interoperable and avoiding various known pitfalls in commonly used schemes. This chapter discusses Public-Key Cryptography Standards (PKCS) which have significant impact on the use of public key cryptography in practice. PKCS standards are a set of standards, called PKCS #1 through #15. These standards cover RSA encryption, RSA signature, password-based encryption, cryptographic message syntax, private-key information syntax, selected object classes and attribute types, certification request syntax, cryptographic token interface, personal information exchange syntax, and cryptographic token information syntax. The PKCS standards are published by RSA Laboratories. Though RSA Laboratories solicits public opinions and advice for PKCS standards, RSA Laboratories retain sole decision-making authority on all aspects of PKCS standards. PKCS has been the basis for many other standards such as S/MIME.
Caspases in synaptic plasticity
Zheng Li, Morgan Sheng
Molecular Brain , 2012, DOI: 10.1186/1756-6606-5-15
Abstract: Caspases are a family of cysteine proteases that have a conserved cysteine residue at their active site and cleave after an aspartate residue in their substrates. As key proteolytic enzymes involved in programmed cell death (or apoptosis), caspases are found in a wide range of animals from worms to humans; in mammals, 12 caspases have been identified. Caspases are generally translated as inactive zymogens and activated through proteolytic cleavage. Based on their structure and function, caspases are classified into two groups: initiator caspases and effector caspases. Initiator caspases (caspase-1, -2, -4, -5, -8, -9, -10, -11 and -12) have a long N-terminal prodomain through which they are recruited to specific protein complexes for activation. Once activated, initiator caspases can cleave and activate downstream effector caspases (e.g. caspase-3, -6, -7, -14), which then go on to proteolyze further cellular substrates, of which many examples are now known [1].Since the discovery of the critical function of the C. elegans caspase ced-3 in programmed cell death [2,3], most members of the caspase family have been demonstrated to be components of apoptotic signaling pathways. The biochemistry and function of these proteases have been predominantly studied in the context of apoptosis. In cells undergoing apoptosis, caspases are activated by two main pathways: the extrinsic pathway and the intrinsic pathway (see Figure 1). The extrinsic pathway is initiated by binding of specific ligands (e.g. tumor necrosis factor alpha [TNFα], Fas ligand, Nerve growth factor [NGF]) to cell surface "death receptors", such as tumor necrosis factor receptor 1 (TNFR1), Fas and nerve growth factor receptor p75NTR [4]. Upon ligand binding, the death receptors multimerize and recruit multiple adaptor molecules to form the death-inducing signaling complex (DISC), which in turn interacts with and activates the initiator caspases [1]. For TNFR1, TNF receptor associated-protein with death domain
Effector Caspases and Leukemia  [PDF]
Ying Lu,Guo-Qiang Chen
International Journal of Cell Biology , 2011, DOI: 10.1155/2011/738301
Abstract: Caspases, a family of aspartate-specific cysteine proteases, play a major role in apoptosis and a variety of physiological and pathological processes. Fourteen mammalian caspases have been identified and can be divided into two groups: inflammatory caspases and apoptotic caspases. Based on the structure and function, the apoptotic caspases are further grouped into initiator/apical caspases (caspase-2, -8, -9, and -10) and effector/executioner caspases (caspase-3, -6, and -7). In this paper, we discuss what we have learned about the role of individual effector caspase in mediating both apoptotic and nonapoptotic events, with special emphasis on leukemia-specific oncoproteins in relation to effector caspases. 1. Introduction The original investigations showed that CED-3 and CED-4 genes play essential roles in either the initiation or execution of the cell death program during the development of the model organism nematode Caenorhabditis elegans (C. elegans). Further study proposed that CED-3 acts as a cysteine protease in controlling the onset of programmed cell death in C. elegans, and the CED-3 protein in C. elegans is similar to human interleukin-1β (IL-1β) converting enzyme (ICE) gene, a cysteine protease that can cleave the 31?kD inactive precursor of IL-1β to generate the active form of cytokine. Overexpression of ICE (currently named caspase-1) is sufficient to induce programmed cell death of mammalian cells, suggesting that members of the CED-3/ICE gene family might function in programmed cell death in vertebrates [1]. With this encouragement, so far fourteen members of mammalian caspase family have been identified [2]. In general, caspase presents within the cell as inactive zymogen that consists of an N-terminal prodomain of variable length, a large subunit (p20), a short linker motif, and a small subunit (p10). In response to apoptotic stimuli, the zymogens are activated through proteolytic processing at specific asparagine residues located within the prodomain, resulting in the generation of active caspases in the form of (p20)2–(p10)2 heterotetramer. Active caspases subsequently initiate apoptosis or inflammatory responses by the cleavage of specific substrates [2, 3]. Based on the structure and function, the caspase family can be divided into three categories. The caspases bearing larger prodomains are inflammatory caspases (caspase-1, -4, -5, -11, -12, -13, and -14) and initiator/apical/upstream of apoptosis caspases (caspase-2, -8, -9, and -10), while caspases with shorter prodomains are effector/executioner/downstream caspases (caspase-3,
GSK3A Is Redundant with GSK3B in Modulating Drug Resistance and Chemotherapy-Induced Necroptosis  [PDF]
Emanuela Grassilli, Leonarda Ianzano, Sara Bonomo, Carola Missaglia, Maria Grazia Cerrito, Roberto Giovannoni, Laura Masiero, Marialuisa Lavitrano
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100947
Abstract: Glycogen Synthase Kinase-3 alpha (GSK3A) and beta (GSK3B) isoforms are encoded by distinct genes, are 98% identical within their kinase domain and perform similar functions in several settings; however, they are not completely redundant and, depending on the cell type and differentiative status, they also play unique roles. We recently identified a role for GSK3B in drug resistance by demonstrating that its inhibition enables necroptosis in response to chemotherapy in p53-null drug-resistant colon carcinoma cells. We report here that, similarly to GSK3B, also GSK3A silencing/inhibition does not affect cell proliferation or cell cycle but only abolishes growth after treatment with DNA-damaging chemotherapy. In particular, blocking GSK3A impairs DNA repair upon exposure to DNA-damaging drugs. As a consequence, p53-null cells overcome their inability to undergo apoptosis and mount a necroptotic response, characterized by absence of caspase activation and RIP1-independent, PARP-dependent AIF nuclear re-localization. We therefore conclude that GSK3A is redundant with GSK3B in regulating drug-resistance and chemotherapy-induced necroptosis and suggest that inhibition of only one isoform, or rather partial inhibition of overall cellular GSK3 activity, is enough to re-sensitize drug-resistant cells to chemotherapy.
The Enigmatic Roles of Caspases in Tumor Development  [PDF]
Richard J?ger,Ralf M. Zwacka
Cancers , 2010, DOI: 10.3390/cancers2041952
Abstract: One function ascribed to apoptosis is the suicidal destruction of potentially harmful cells, such as cancerous cells. Hence, their growth depends on evasion of apoptosis, which is considered as one of the hallmarks of cancer. Apoptosis is ultimately carried out by the sequential activation of initiator and executioner caspases, which constitute a family of intracellular proteases involved in dismantling the cell in an ordered fashion. In cancer, therefore, one would anticipate caspases to be frequently rendered inactive, either by gene silencing or by somatic mutations. From clinical data, however, there is little evidence that caspase genes are impaired in cancer. Executioner caspases have only rarely been found mutated or silenced, and also initiator caspases are only affected in particular types of cancer. There is experimental evidence from transgenic mice that certain initiator caspases, such as caspase-8 and -2, might act as tumor suppressors. Loss of the initiator caspase of the intrinsic apoptotic pathway, caspase-9, however, did not promote cellular transformation. These data seem to question a general tumor-suppressive role of caspases. We discuss several possible ways how tumor cells might evade the need for alterations of caspase genes. First, alternative splicing in tumor cells might generate caspase variants that counteract apoptosis. Second, in tumor cells caspases might be kept in check by cellular caspase inhibitors such as c-FLIP or XIAP. Third, pathways upstream of caspase activation might be disrupted in tumor cells. Finally, caspase-independent cell death mechanisms might abrogate the selection pressure for caspase inactivation during tumor development. These scenarios, however, are hardly compatible with the considerable frequency of spontaneous apoptosis occurring in several cancer types. Therefore, alternative concepts might come into play, such as compensatory proliferation. Herein, apoptosis and/or non-apoptotic functions of caspases may even promote tumor development. Moreover, experimental evidence suggests that caspases might play non-apoptotic roles in processes that are crucial for tumorigenesis, such as cell proliferation, migration, or invasion. We thus propose a model wherein caspases are preserved in tumor cells due to their functional contributions to development and progression of tumors.
DNA-PKcs plays a dominant role in the regulation of H2AX phosphorylation in response to DNA damage and cell cycle progression
Jing An, Yue-Cheng Huang, Qing-Zhi Xu, Li-Jun Zhou, Zeng-Fu Shang, Bo Huang, Yu Wang, Xiao-Dan Liu, De-Chang Wu, Ping-Kun Zhou
BMC Molecular Biology , 2010, DOI: 10.1186/1471-2199-11-18
Abstract: The level of γH2AX in HeLa cells increased rapidly with a peak level at 0.25 - 1.0 h after 4 Gy γ irradiation. SiRNA-mediated depression of DNA-PKcs resulted in a strikingly decreased level of γH2AX. An increased γH2AX was also induced in the ATM deficient cell line AT5BIVA at 0.5 - 1.0 h after 4 Gy γ rays, and this IR-increased γH2AX in ATM deficient cells was dramatically abolished by the PIKK inhibitor wortmannin and the DNA-PKcs specific inhibitor NU7026. A high level of constitutive expression of γH2AX was observed in another ATM deficient cell line ATS4. The alteration of γH2AX level associated with cell cycle progression was also observed. HeLa cells with siRNA-depressed DNA-PKcs (HeLa-H1) or normal level DNA-PKcs (HeLa-NC) were synchronized at the G1 phase with the thymidine double-blocking method. At ~5 h after the synchronized cells were released from the G1 block, the S phase cells were dominant (80%) for both HeLa-H1 and HeLa-NC cells. At 8 - 9 h after the synchronized cells released from the G1 block, the proportion of G2/M population reached 56 - 60% for HeLa-NC cells, which was higher than that for HeLa H1 cells (33 - 40%). Consistently, the proportion of S phase for HeLa-NC cells decreased to ~15%; while a higher level (26 - 33%) was still maintained for the DNA-PKcs depleted HeLa-H1 cells during this period. In HeLa-NC cells, the γH2AX level increased gradually as the cells were released from the G1 block and entered the G2/M phase. However, this γH2AX alteration associated with cell cycle progressing was remarkably suppressed in the DNA-PKcs depleted HeLa-H1 cells, while wortmannin and NU7026 could also suppress this cell cycle related phosphorylation of H2AX. Furthermore, inhibition of GSK3β activity with LiCl or specific siRNA could up-regulate the γH2AX level and prolong the time of increased γH2AX to 10 h or more after 4 Gy. GSK3β is a negative regulation target of DNA-PKcs/Akt signaling via phosphorylation on Ser9, which leads to its inactivat
Selective cyclooxygenase-2 inhibitor celecoxib could sensitize B-cell-originated lymphoma cell lines to epirubicin via down-regulation of MDR-1 mRNA and Bcl-2 mRNA expression

HUA Fanli
, WANG Lingyan, ZHAO Xin, et al

- , 2015, DOI: 10.3969/j.issn.1007-3969.2015.06.005
Abstract: 背景与目的:部分非霍奇金淋巴瘤(non-Hodgkin’s lymphoma, NHL)具有高表达环氧合酶-2(cyclooxygenase-2,COX-2)的特征,而后者与P-糖蛋白及Bcl-2表达相关,可能导致NHL对化疗耐药。本研究旨在探讨B细胞淋巴瘤细胞株中COX-2的表达以及选择性COX-2抑制剂塞来昔布增强淋巴瘤细胞对表柔比星抗肿瘤效应的敏感性及其可能机制。方法:用荧光定量PCR(qRT-PCR)及蛋白[质]印迹法(Western blot)分别检测Raji、Jeko-1和Namalwa等淋巴瘤细胞株以及正常人外周血B细胞的COX-2表达;以梯度浓度的塞来昔布作用于淋巴瘤细胞株,CCK-8方法检测细胞增殖的抑制程度,qRT-PCR检测各细胞株MDR-1 mRNA及Bcl-2 mRNA表达的变化;表柔比星单独或联合不同浓度的塞来昔布处理Raji细胞株72 h后,CCK-8方法分析塞来昔布对表柔比星的增敏作用。结果:各淋巴瘤细胞株及正常对照外周血B细胞均不表达COX-2。塞来昔布单药即可对各淋巴瘤细胞株产生程度不同的抗增殖效应;随着塞来昔布作用浓度的增加,除Jeko-1细胞不表达MDR-1外,其余细胞株MDR-1 mRNA及Bcl-2 mRNA表达水平逐渐下降;塞来昔布明显增强表柔比星对Raji细胞的抗肿瘤活性,两者之间具有协同作用。结论:选择性COX-2抑制剂塞来昔布下调B细胞淋巴瘤细胞株的MDR-1 mRNA及Bcl-2 mRNA水平,并且增强表柔比星对淋巴瘤细胞的抗肿瘤效应。
Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy
Shadi Mamaghani, Satish Patel, David W Hedley
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-132
Abstract: GSK-3 inhibition was achieved using the pharmacological agent AR-A014418 or siRNA against GSK-3 alpha and beta isoforms. Cytotoxicity was measured using a Sulphorhodamine B assay and clonogenic survival following exposure of six different pancreatic cancer cell lines to a range of doses of either gemcitabine, AR-A014418 or both for 24, 48 and 72 h. We measured protein expression levels by immunoblotting. Basal and TNF-alpha induced activity of NF-kappaB was assessed using a luciferase reporter assay in the presence or absence of GSK-3 inhibition.GSK-3 inhibition reduced both basal and TNF-alpha induced NF-kappaB luciferase activity. Knockdown of GSK-3 beta reduced nuclear factor kappa B luciferase activity to a greater extent than GSK-3 alpha, and the greatest effect was seen with dual knockdown of both GSK-3 isoforms. GSK-3 inhibition also resulted in reduction of the NF-kappaB target proteins XIAP, Bcl-XL, and cyclin D1, associated with growth inhibition and decreased clonogenic survival. In all cell lines, treatment with either AR-A014418, or gemcitabine led to growth inhibition in a dose- and time-dependent manner. However, with the exception of PANC-1 where drug synergy occurred with some dose schedules, the inhibitory effect of combined drug treatment was additive, sub-additive, or even antagonistic.GSK-3 inhibition has anticancer effects against pancreatic cancer cells with a range of genetic backgrounds associated with disruption of NF-kappaB, but does not significantly sensitize these cells to the standard chemotherapy agent gemcitabine. This lack of synergy might be context or cell line dependent, but could also be explained on the basis that although NF-kappaB is an important mediator of pancreatic cancer cell survival, it plays a minor role in gemcitabine resistance. Further work is needed to understand the mechanisms of this effect, including the potential for rational combination of GSK3 inhibitors with other targeted agents for the treatment of pancre
Novel Reporter Alleles of GSK-3α and GSK-3β  [PDF]
William B. Barrell, Heather L. Szabo-Rogers, Karen J. Liu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050422
Abstract: Glycogen Synthase Kinase 3 (GSK-3) is a key player in development, physiology and disease. Because of this, GSK-3 inhibitors are increasingly being explored for a variety of applications. In addition most analyses focus on GSK-3β and overlook the closely related protein GSK-3α. Here, we describe novel GSK-3α and GSK-3β mouse alleles that allow us to visualise expression of their respective mRNAs by tracking β-galactosidase activity. We used these new lacZ alleles to compare expression in the palate and cranial sutures and found that there was indeed differential expression. Furthermore, both are loss of function alleles and can be used to generate homozygous mutant mice; in addition, excision of the lacZ cassette from GSK-3α creates a Cre-dependent tissue-specific knockout. As expected, GSK3α mutants were viable, while GSK3β mutants died after birth with a complete cleft palate. We also assessed the GSK-3α mutants for cranial and sternal phenotypes and found that they were essentially normal. Finally, we observed gestational lethality in compound GSK-3β?/?; GSK3α+/? mutants, suggesting that GSK-3 dosage is critical during embryonic development.
GSK-3 in Neurodegenerative Diseases  [PDF]
Peng Lei,Scott Ayton,Ashley I. Bush,Paul A. Adlard
International Journal of Alzheimer's Disease , 2011, DOI: 10.4061/2011/189246
Abstract: Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes, and its dysregulation is implicated in the pathogenesis of diverse diseases. In this paper we will focus on the dysfunction of GSK-3 in Alzheimer’s disease and Parkinson’s disease. Specifically, GSK-3 is known to interact with tau, β-amyloid (Aβ), and α-synuclein, and as such may be crucially involved in both diseases. Aβ production, for example, is regulated by GSK-3, and its toxicity is mediated by GSK-induced tau phosphorylation and degeneration. α-synuclein is a substrate for GSK-3 and GSK-3 inhibition protects against Parkinsonian toxins. Lithium, a GSK-3 inhibitor, has also been shown to affect tau, Aβ, and α-synuclein in cell culture, and transgenic animal models. Thus, understanding the role of GSK-3 in neurodegenerative diseases will enhance our understanding of the basic mechanisms underlying the pathogenesis of these disorders and also facilitate the identification of new therapeutic avenues. 1. Introduction: GSK-3 Isoforms, Expression, and Neuronal Regulation Glycogen synthase kinase-3 (GSK-3) is a cellular serine/threonine protein kinase [1, 2], belonging to the glycogen synthase kinase family [1]. It is involved in a number of cellular processes, including the division, proliferation, differentiation, and adhesion of cells [3]. Dysfunction of GSK-3 is implicated in diverse human diseases, including Alzheimer’s disease (AD), Parkinson’s Disease (PD), type 2 diabetes, bipolar disorder (BPD), and cancer [3, 4]. Two isoforms of GSK-3 have been identified, namely, GSK-3α and GSK-3β, which although encoded by different genes are similarly regulated [5]. GSK-3α (51?kDa) differs to GSK-3β (47?kDa) in that the former has a glycine-rich extension at the amino-terminal end of the protein [5]. Both isoforms are ubiquitously expressed throughout the brain, with high levels of expression seen in the hippocampus, cerebral cortex, and the Purkinje cells of the cerebellum [6]. The expression ratio of these isoforms, however, favors GSK-3β [6, 7]. The crystal structure of GSK-3β reveals a catalytically active dimer [8] conformation that progressively phosphorylates substrates with Ser/Thr pentad repeats [9]. Despite having disparate sequences, the isoforms have a conserved functional domain and share similar substrates, while remaining pharmacologically distinguishable [3]. The independent deletion of GSK-3 isoforms in mice resulted in a distinct profile of substrate phosphorylation [10], suggesting different functions of GSK-3 isoforms in the brain. The activity of GSK-3 is dependent
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