bluuebunny/crossref_metadata_2025_split huggingface dataset:
Src Phosphorylates Tyr284 in TGF-β Type II Receptor and Regulates TGF-β Stimulation of p38 MAPK during Breast Cancer Cell Proliferation and Invasion
Authors: Galliher Amy J. , Schiemann William P. 
Published: April 2007

Abstract
Genetic and epigenetic events often negate the cytostatic function of transforming growth factor-β (TGF-β) in mammary epithelial cells (MEC), which ultimately enables malignant MECs to proliferate, invade, and metastasize when stimulated by TGF-β. The molecular mechanisms underlying this phenotypic conversion of TGF-β function during mammary tumorigenesis remain poorly defined. We previously established αvβ3 integrin and Src as essential mediators of mitogen-activated protein kinase (MAPK) activation, invasion, and epithelial-to-mesenchymal transition stimulated by TGF-β in normal and malignant MECs. Mechanistically, β3 integrin interacted physically with the TGF-β type II receptor (TβR-II), leading to its tyrosine phosphorylation by Src and the initiation of oncogenic signaling by TGF-β. We now show herein that Src phosphorylated TβR-II on Y284 both in vitro and in vivo. Interestingly, although the expression of Y284F-TβR-II mutants in breast cancer cells had no effect on TGF-β stimulation of Smad2/3, this TβR-II mutant completely abrogated p38 MAPK activation by TGF-β. Accordingly, Src-mediated phosphorylation of Y284 coordinated the docking of the SH2 domains of growth factor receptor binding protein 2 (Grb2) and Src homology domain 2 containing (Shc) TβR-II, thereby associating these adapter proteins to MAPK activation by TGF-β. Importantly, Y284F-TβR-II mutants also abrogated breast cancer cell invasion induced by αvβ3 integrin and TGF-β as well as partially restored their cytostatic response to TGF-β. Our findings have identified a novel αvβ3 integrin/Src/Y284/TβR-II signaling axis that promotes oncogenic signaling by TGF-β in malignant MECs and suggest that antagonizing this signaling axis may one day prove beneficial in treating patients with metastatic breast cancers. [Cancer Res 2007;67(8):3752–8]
Identification of Their Epitope Reveals the Structural Basis for the Mechanism of Action of the Immunosuppressive Antibodies Basiliximab and Daclizumab
Authors: Binder Mascha , Vögtle Friederike-Nora , Michelfelder Stefan , Müller Fabian , Illerhaus Gerald , Sundararajan Sangeeth , Mertelsmann Roland , Trepel Martin 
Published: April 2007

AbstractInterleukin-2 (IL-2) and its receptor (IL-2R) play a major role in cellular immunity. The monoclonal antibodies basiliximab and daclizumab directed against the IL-2R subunit CD25 are widely used to prevent graft or host rejection after allogeneic tissue transplantation. Although these antibodies have been used for this purpose for many years, their common epitope within the CD25 protein is unknown. We screened a random phage display library to isolate peptides specifically binding to basiliximab. A striking amino acid sequence motif was enriched. This motif is homologous to the peptide ERIYHFV comprising amino acid positions 116 to 122 within the extracellular domain of CD25, suggesting that this is the basiliximab epitope. Basiliximab and daclizumab binding of selected phage was specific, as no binding was observed to isotype antibody controls. Phage binding could be inhibited by the cognate peptide. In cells expressing mutant CD25, binding of basiliximab was abolished when two or more amino acids of the suspected epitope were changed. In contrast, basiliximab binding remained unaffected in cells expressing CD25 versions with mutations outside this epitope. We therefore conclude that the (116)ERIYHFV(122) string within CD25 is the epitope recognized by basiliximab and daclizumab. This epitope overlaps with the interaction site of CD25 and IL-2, thus revealing the structural basis for the inhibition of IL-2R binding by this class of immunosuppressive antibodies. [Cancer Res 2007;67(8):3518–23]
P21-Activated Protein Kinase Is Overexpressed in Hepatocellular Carcinoma and Enhances Cancer Metastasis Involving c-Jun NH2-Terminal Kinase Activation and Paxillin Phosphorylation
Authors: Ching Yick-Pang , Leong Veronica Y.L. , Lee Man-Fong , Xu Hai-Tao , Jin Dong-Yan , Ng Irene Oi-Lin 
Published: April 2007

Abstract
Hepatocellular carcinoma (HCC) is one of the major malignancies in the world. The prognosis of HCC is poor, due to frequent intrahepatic metastasis and tumor recurrence. P21-activated protein kinase (Pak1), a main downstream effector of small Rho GTPases, Rac1 and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Here, we show that Pak1 gene was overexpressed in human HCCs. Overexpression of Pak1 in human HCCs was associated with more aggressive tumor behavior in terms of more metastatic phenotype and more advanced tumor stages. In addition, HCC cell line stably expressing Pak1 displayed increased cell motility rates and, conversely, knockdown of endogenous Pak1 expression by small interfering RNA reduced the migration rates of HCC cells. In an established metastatic HCC cell line, we found that Pak1 was overexpressed compared with its primary HCC cell line and this overexpression was associated with higher cell motility. Importantly, we found that c-Jun NH2-terminal kinase (JNK) was activated in HCC cell lines overexpressing Pak1. Inhibition of the JNK activity by chemical inhibitor significantly reduced the migration rates of HCC cells via attenuation of paxillin phosphorylation at Ser178. In conclusion, our results document that Pak1 is overexpressed in HCCs and plays an important role in the metastasis of HCC. The mechanism by which Pak1 induces cancer metastasis may involve activation of JNK and phosphorylation of paxillin. [Cancer Res 2007;67(8):3601–8]
Tumor Necrosis Factor Receptor 1/c-Jun-NH2-Kinase Signaling Promotes Human Neoplasia
Authors: Zhang Jennifer Y. , Adams Amy E. , Ridky Todd W. , Tao Shiying , Khavari Paul A. 
Published: April 2007

Abstract
The tumor necrosis factor α receptor (TNFR1) activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH2-kinase (JNK)/activator protein 1 (AP1) cascade. Here, we report that JNK is activated in a majority of spontaneous human squamous cell carcinomas (SCC). JNK pathway induction bypassed cell cycle restraints induced by oncogenic Ras and cooperated with Ras to convert normal human epidermis into tumors indistinguishable from SCC, confirming its oncogenic potency in human tissue. Inhibiting MKK7, JNK, and AP1 as well as TNFR1 itself using genetic, pharmacologic, or antibody-mediated approaches abolished invasive human epidermal neoplasia in a tumor cell autonomous fashion. The TNFR1/MKK7/JNK/AP1 cascade thus promotes human neoplasia and represents a potential therapeutic target for human epithelial cancers. [Cancer Res 2007;67(8):3827–34]
SAG/ROC2/Rbx2 Is a Novel Activator Protein-1 Target that Promotes c-Jun Degradation and Inhibits 12-O-Tetradecanoylphorbol-13-Acetate–Induced Neoplastic Transformation
Authors: Gu Qingyang , Tan Mingjia , Sun Yi 
Published: April 2007

Abstract
SAG (sensitive to apoptosis gene) was first identified as a stress-responsive protein that, when overexpressed, inhibited apoptosis both in vitro and in vivo. SAG was later found to be the second family member of ROC1 or Rbx1, a RING component of SCF and DCX E3 ubiquitin ligases. We report here that SAG/ROC2/Rbx2 is a novel transcriptional target of activator protein-1 (AP-1). AP-1 bound both in vitro and in vivo to two consensus binding sites in a 1.3-kb region of the mouse SAG promoter. The SAG promoter activity, as measured by luciferase reporter assay, was dependent on these sites. Consistently, endogenous SAG is induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) with an induction time course following the c-Jun induction in both mouse epidermal JB6-Cl.41 and human 293 cells. TPA-mediated SAG induction was significantly reduced in JB6-Cl.41 cells overexpressing a dominant-negative c-Jun, indicating a requirement of c-Jun/AP-1. On the other hand, SAG seemed to modulate the c-Jun levels. When overexpressed, SAG remarkably reduced both basal and TPA-induced c-Jun levels, whereas SAG small interfering RNA (siRNA) silencing increased substantially the levels of both basal and TPA-induced c-Jun. Consistently, SAG siRNA silencing reduced c-Jun polyubiquitination and blocked c-Jun degradation induced by Fbw7, an F-box protein of SCF E3 ubiquitin ligase. Finally, SAG overexpression inhibited, whereas SAG siRNA silencing enhanced, respectively, the TPA-induced neoplastic transformation in JB6-Cl.41 preneoplastic model. Thus, AP-1/SAG establishes an autofeedback loop, in which on induction by AP-1, SAG promotes c-Jun ubiquitination and degradation, thus inhibiting tumor-promoting activity of AP-1. [Cancer Res 2007;67(8):3616–10]
Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens
Authors: Doak Shareen H. , Jenkins Gareth J.S. , Johnson George E. , Quick Emma , Parry Elizabeth M. , Parry James M. 
Published: April 2007

Abstract
A mechanistic understanding of carcinogenic genotoxicity is necessary to determine consequences of chemical exposure on human populations and improve health risk assessments. Currently, linear dose-responses are assumed for DNA reactive compounds, ignoring cytoprotective processes that may limit permanent damage. To investigate the biological significance of low-dose exposures, human lymphoblastoid cells were treated with alkylating agents that have different mechanisms of action and DNA targets: methylmethane sulfonate (MMS), methylnitrosourea (MNU), ethylmethane sulfonate (EMS), and ethylnitrosourea (ENU). Chromosomal damage and point mutations were quantified with the micronucleus and hypoxanthine phosphoribosyltransferase forward mutation assays. MNU and ENU showed linear dose-responses, whereas MMS and EMS had nonlinear curves containing a range of nonmutagenic low doses. The lowest observed effect level for induction of chromosomal aberrations was 0.85 μg/mL MMS and 1.40 μg/mL EMS; point mutations required 1.25 μg/mL MMS and 1.40 μg/mL EMS before a mutagenic effect was detected. This nonlinearity could be due to homeostatic maintenance by DNA repair, which is efficient at low doses of compounds that primarily alkylate N7-G and rarely attack O atoms. A pragmatic threshold for carcinogenicity may therefore exist for such genotoxins. [Cancer Res 2007;67(8):3904–11]
Molecular Mechanisms Underlying FIP1L1-PDGFRA–Mediated Myeloproliferation
Authors: Buitenhuis Miranda , Verhagen Liesbeth P. , Cools Jan , Coffer Paul J. 
Published: April 2007

Abstract
An interstitial deletion on chromosome 4q12 resulting in the formation of the FIP1L1-PDGFRA fusion protein is involved in the pathogenesis of imatinib-sensitive chronic eosinophilic leukemia. The molecular mechanisms underlying the development of disease are largely undefined. Human CD34+ hematopoietic progenitor cells were used to investigate the role of FIP1L1-PDGFRA in modulating lineage development. FIP1L1-PDGFRA induced both proliferation and differentiation of eosinophils, neutrophils, and erythrocytes in the absence of cytokines, which could be inhibited by imatinib. Whereas expression of FIP1L1-PDGFRA in hematopoietic stem cells and common myeloid progenitors induced the formation of multiple myeloid lineages, expression in granulocyte-macrophage progenitors induced only the development of eosinophils, neutrophils, and myeloblasts. Deletion of amino acids 30 to 233 in the FIP1L1 gene [FIP1L1(1–29)-PDGFRA] gave rise to an intermediate phenotype, exhibiting a dramatic reduction in the number of erythrocytes. FIP1L1-PDGFRA and FIP1L1(1–29)-PDGFRA both induced the activation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) in myeloid progenitors, whereas signal transducers and activators of transcription 5 (STAT5) and protein kinase B/c-akt were only activated by FIP1L1-PDGFRA. Dominant-negative STAT5 partially inhibited FIP1L1-PDGFRA–induced colony formation, whereas combined inhibition of phosphatidylinositol-3-kinase and ERK1/2 significantly reversed FIP1L1-PDGFRA–induced colony formation. Taken together, these results suggest that expression of FIP1L1-PDFGRA in human hematopoietic progenitors induce a myeloproliferative phenotype via activation of multiple signaling molecules including phosphatidylinositol-3-kinase, ERK1/2, and STAT5. [Cancer Res 2007;67(8):3759–66]
Malignant Glioma Cells Counteract Antitumor Immune Responses through Expression of Lectin-Like Transcript-1
Authors: Roth Patrick , Mittelbronn Michel , Wick Wolfgang , Meyermann Richard , Tatagiba Marcos , Weller Michael 
Published: April 2007

AbstractGlioblastoma, one of the most lethal tumors, is paradigmatic for tumor-associated immunosuppression. Lectin-like transcript-1 (LLT1) is a newly identified ligand for the inhibitory natural killer (NK) cell receptor CD161. Here, we report that glioma cells express LLT1 mRNA and protein in vitro and in vivo, whereas expression levels in normal brain are low. LLT1 expression in human gliomas increases with the WHO grade of malignancy. We further show that transforming growth factor-β (TGF-β) up-regulates the expression of LLT1 in glioma cells. Small interfering RNA (siRNA)–mediated down-regulation of LLT1 in LNT-229 and LN-428 cells promotes their lysis by NK cells. Thus, LLT1 acts as a mediator of immune escape and contributes to the immunosuppressive properties of glioma cells. [Cancer Res 2007;67(8):3540–4]
The Determinants of Employee-Involvement Schemes: Private Sector Australian Evidence
Authors: Brown Michelle , Geddes Lori A. , Heywood John S. 
Published: April 2007

Using data from the 1995 wave of the Australian Workplace Industrial Relations Survey, this article estimates the determinants of four types of group employee-involvement (EI) schemes: autonomous groups, quality circles, joint consultative committees and task forces. The results indicate that EI is associated with employees having longer expected tenure and higher labour force attachment. The authors argue that this is sensible as EI will be more successful in settings of interdependent production, settings in which such employees are at a premium. The results also show that complementary HRM practices, such as formal training and incentive pay, are associated with an increased likelihood of EI. Unionization, size of workplace and the extent of competition are also confirmed as determinants.
Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study
Authors: Galli Monica , Borrelli Giovanna , Jacobsen Eva Marie , Marfisi Rosa Maria , Finazzi Guido , Marchioli Roberto , Wisloff Finn , Marziali Stefana , Morboeuf Olivier , Barbui Tiziano 
Published: April 2007

Abstract
To assess the clinical significance of lupus anticoagulants (LAs) and antiphospholipid antibodies (aPLs) toward thrombosis and abortions, we measured them in 112 patients whose samples were available at enrollment in the warfarin in the antiphospholipid syndrome (WAPS) study. Enzyme-linked immunosorbent assay (ELISA) and coagulation test values in the highest and lowest tertiles were compared. When considered separately, IgG antibodies to β2-glycoprotein I (aβ2GPI) and prothrombin (aPT) were associated with anamnestic arterial and venous thrombosis, respectively, and those to annexin AV (aAnAV) with abortions. IgM antibodies to protein S and the lupus ratio of the dilute prothrombin time were associated with prospective thrombosis. No other association for IgM antibodies was seen. LA-positive patients who carried aβ2GPI antibodies were at risk of anamnestic arterial and total thrombosis and aPT antibodies to that of anamnestic venous and total thrombosis. LA-positive patients who carried IgG aβ2GPI and aAnAV antibodies were at risk for both anamnestic abortion and prospective thrombosis. Overall, these data support the inclusion of aβ2GPI antibodies in and suggest the removal of anticardiolipin antibodies from the laboratory criteria of the antiphospholipid syndrome. They also suggest that the measurement of aPT and aAnAV antibodies is useful in some selected situations and that there is little role for IgM antibody detection.
Galectin-1 mediated suppression of Epstein-Barr virus–specific T-cell immunity in classic Hodgkin lymphoma
Authors: Gandhi Maher K. , Moll Guido , Smith Corey , Dua Ujjwal , Lambley Eleanore , Ramuz Olivier , Gill Devinder , Marlton Paula , Seymour John F. , Khanna Rajiv 
Published: April 2007

AbstractIn Hodgkin lymphoma (HL), the malignant Hodgkin Reed-Sternberg cells interact with the host microenvironment to create an immunosuppressive network that protects the lymphoma from immune attack. These mechanisms are not fully understood. We examined the role of the immunomodulatory protein galectin-1 (Gal-1) on Epstein-Barr virus-specific CD8+ T cell responses in HL. Initial studies indicated Gal-1 expression in all in vitro established Hodgkin Reed-Sternberg cell lines. In situ analysis revealed Gal-1 expression in 26 of 42 classic HL, whereas Gal-1 was uniformly negative in nodular lymphocyte predominant HL. Gal-1hi expression was associated with male gender, older patients, reduced CD8+ T cell infiltration at the tumor site, and most importantly, an impaired latent membrane protein 1 and 2-specific CD8+ T-cell responses. In vitro exposure to recombinant Gal-1 inhibited proliferation and interferon-γ expression by Epstein-Barr virus-specific T cells. These observations provide an important link between the Gal-1-mediated immunomodulatory networks and loss of antigen-specific T-cell function in classic HL.
Development of huperzine A and B for treatment of Alzheimer's disease
Authors: Bai Donglu 
Published: April 2007

Abstract
Recent studies have proved that huperzine A (HupA) possesses different pharmacological actions other than the inhibition of hydrolysis of ACh. These noncholinergic roles, for instance, the antagonist effect on NMDA receptor, the protection of neuronal cells against β-amyloid, free radicals, and hypoxia-ischemia-induced injury, could be important too in Alzheimer's disease (AD) treatment. The therapeutic effects of HupA are probably based on a multitarget mechanism. By targeting dual active sites of AChE, a series of bis- and bifunctional HupB compounds with various lengths of tether were designed, synthesized, and tested for the inhibition and selectivity of AChE. The most potent bis-HupB compound exhibited increase by three orders of magnitude in AChE inhibition and two orders of magnitude in selectivity for AChE than its parent HupB.
Recent heterocyclic compounds from marine invertebrates: Structure and synthesis
Authors: Kashman Yoel , Rudi Amira , Pappo Doron 
Published: April 2007

Abstract
A large variety of unique heterocyclic natural marine products, without terrestrial counterparts, have been isolated from marine invertebrates, mainly sponges, ascidians, and soft corals. Many of these compounds display interesting biological activity. In this review, we report our recent studies on nitrogen-containing heterocyclic compounds ("alkaloids"), as well as some containing sulfur and oxygen, which have been isolated from Red Sea and Indo-Pacific organisms, and discuss progress on the synthesis of these natural products and structural analogs.
Structural development studies of nuclear receptor ligands
Authors: Hosoda Shinnosuke , Hashimoto Yuichi 
Published: April 2007

Abstract
Studies in our laboratory are focused on structural development studies of biological response modifiers (BRMs), including nuclear receptor (NR) ligands, which act directly on cells at the gene expression level, and thalidomide (and related molecules), which modulates a variety of physiological processes. Our studies on the molecular design of ligands for retinoic acid receptor (RAR), androgen receptor (AR), vitamin D receptor (VDR), farnesoid X receptor (FXR), and peroxisome proliferator-activated receptor (PPAR) are reviewed.
Synthesis of natural products and analogs using multiple Pd-catalyzed transformations
Authors: Tietze Lutz F. , Kinzel Tom 
Published: April 2007

Abstract
Palladium-catalyzed transformations are of great importance in modern synthetic organic chemistry. The vast number of reactions that can be catalyzed by Pd0- as well as Pd2+-complexes in combination with the relative stability of the intermediates offers the intriguing opportunity of carrying out multiple consecutive bond-forming processes. They can be even performed in a domino fashion and in the presence of chiral ligands to allow the efficient preparation of almost enantiopure compounds. In this article, the use of double Heck, Tsuji-Trost-Heck, and Wacker-Heck reactions for the total syntheses of estradiol, spinosyn A analogs, cephalotaxine, and vitamin E is described.
Progress toward a total synthesis of spirastrellolide A
Authors: Paterson Ian , Anderson Edward A. , Dalby Stephen M. , Lim Jong Ho , Loiseleur Olivier , Maltas Philip , Moessner Christian 
Published: April 2007

Abstract
Progress toward a total synthesis of spirastrellolide A, a 38-membered marine macrolide, is reported. Syntheses of two diastereomers of the C1-C25 region, and an evolving Sharpless dihydroxylation strategy toward a C26-C40 fragment, are described. The syntheses exploit boron-mediated aldol chemistry to install key stereocenters, and feature late-stage thermodynamically controlled spiroacetalizations.
Modern pharmacognosy: Connecting biology and chemistry
Authors: Bohlin Lars , Göransson Ulf , Backlund Anders 
Published: April 2007

Abstract
In many countries today, the number of students selecting chemistry for higher studies is decreasing. At the same time, interest in the environmental aspects of chemistry, green chemistry, and sustainable use of natural products is increasing among the young generation of students. By modernizing and renewing a venerable proven science, pharmacognosy would have a strategic position to connect biology and chemistry. This multidisciplinary subject is important for discovery of novel and unique molecules with drug potential, and for revealing unknown targets, by studying evolutionary structure-activity optimization in nature. In this paper, the overall aim and strategies of our research are presented and exemplified by three different research projects.
Natural products are involved in scientific issues important for a sustainable society, and a multidisciplinary subject such as pharmacognosy can, therefore, be useful in increasing future interest in both chemistry and biology.
Manipulating nature's sugar biosynthetic machineries for glycodiversification of macrolides: Recent advances and future prospects
Authors: Thibodeaux Christopher J. , Liu Hung-wen 
Published: April 2007

Abstract
Changing the sugar structures and glycosylation patterns of natural products is an effective means of altering the biological activity of clinically useful drugs. Several recent strategies have provided researchers with the opportunity to manipulate sugar structures and to change the sugar moieties attached to these natural products via a biosynthetic approach. In this review, we explore the utility of contemporary in vivo and in vitro methods to achieve natural product glycodiversification. This study will focus on recent progress from our laboratory in elucidating the biosynthesis of D-desosamine, a deoxysugar component of many macrolide antibiotics, and will highlight how we have engineered the D-desosamine biosynthetic pathway in Streptomyces venezuelae through targeted disruption and heterologous expression of the sugar biosynthetic genes to generate a variety of new glycoforms. The in vitro exploitation of the substrate flexibility of the endogenous D-desosamine glycosyltransferase (GT) to generate many non-natural glycoforms will also be discussed. These experiments are compared with recent work from other research groups on the same topics. Finally, the significance of these studies for the future prospects of natural product glycodiversification is discussed.