bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered IFNγ Signaling and Preserved Susceptibility to Activated Natural Killer Cell–Mediated Lysis of BCR/ABL Targets
Authors: Cebo Christelle , Voutsadakis Ioannis A. , Da Rocha Sylvie , Bourhis Jean-Henri , Jalil Abdelali , Azzarone Bruno , Turhan Ali G. , Chelbi-Alix Mounira , Chouaib Salem , Caignard Anne 
Published: September 2005

Abstract
Previous studies have shown that BCR/ABL oncogene, the molecular counterpart of the Ph1 chromosome, could represent a privileged target to natural killer (NK) cells. In the present study, we showed that activated peripheral NK cells killed high-level BCR/ABL transfectant UT-7/9 derived from the pluripotent hematopoietic cell line UT-7 with a high efficiency. To further define the mechanisms controlling BCR/ABL target susceptibility to NK-mediated lysis, we studied the effect of IFNγ, a key cytokine secreted by activated NK cells, on the lysis of these targets. Treatment of UT-7, UT-7/neo, and low BCR/ABL transfectant UT-7/E8 cells with IFNγ resulted in a dramatic induction of human leukocyte antigen class I (HLA-I) molecules and subsequently in their reduced susceptibility to NK-mediated cytolysis likely as a consequence of inhibitory NK receptors engagement. In contrast, such treatment neither affected HLA-I expression on transfectants expressing high level of BCR/ABL (UT-7/9) nor modulated their lysis by NK cells. Our data further show that the high-level BCR/ABL in UT-7/9 cells display an altered IFNγ signaling, as evidenced by a decrease in IFN regulatory factor-1 (IRF-1) and signal transducers and activators of transcription (STAT) 1 induction and activation in response to IFNγ, whereas this pathway is normal in UT-7 and UT-7/E8 cells. A decreased HLA-I induction and nuclear phospho-STAT1 nuclear translocation were also observed in blasts from most chronic myelogenous leukemia patients in response to IFNγ. These results outline the crucial role of IFNγ in the control of target cell susceptibility to lysis by activated NK cells and indicate that the altered response to IFNγ in BCR/ABL targets may preserve these cells from the cytokine-induced negative regulatory effect on their susceptibility to NK-mediated lysis.
The Androgen Derivative 5α-Androstane-3β,17β-Diol Inhibits Prostate Cancer Cell Migration Through Activation of the Estrogen Receptor β Subtype
Authors: Guerini Vittoria , Sau Daniela , Scaccianoce Eugenia , Rusmini Paola , Ciana Paolo , Maggi Adriana , Martini Paolo G.V. , Katzenellenbogen Benita S. , Martini Luciano , Motta Marcella , Poletti Angelo 
Published: September 2005

Abstract
Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5α-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor–independent mechanism. We have shown that the dihydrotestosterone metabolite 5α-androstane-3β,17β-diol (3β-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor β (ERβ), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERβ signaling. Very surprisingly, estradiol is not active, suggesting the existence of different pathways for ERβ activation in prostate cancer cells. Moreover, 3β-Adiol, through ERβ, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3β-Adiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that (a) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and (b) that the estrogenic effect of testosterone derivatives (ERβ-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estradiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3β-hydroxysteroid dehydrogenases (the enzymes responsible for 3β-Adiol formation) are strongly correlated with hereditary prostate cancer.
Identification of Src-Specific Phosphorylation Site on Focal Adhesion Kinase: Dissection of the Role of Src SH2 and Catalytic Functions and Their Consequences for Tumor Cell Behavior
Authors: Brunton Valerie G. , Avizienyte Egle , Fincham Valerie J. , Serrels Bryan , Metcalf Chester A. , Sawyer Tomi K. , Frame Margaret C. 
Published: September 2005

Abstract
Src tyrosine kinase expression and activity are elevated during colon cancer progression. How this contributes to the malignant phenotype is not fully understood. We show that in KM12C colon carcinoma cells, expression of kinase-deficient Src proteins (SrcMF and Src251) does not alter cell growth. Src kinase activity is required for turnover of cell-matrix adhesions and, in particular, the Src-dependent phosphorylation of focal adhesion kinase (FAK) is required for their disassembly. Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr407, Tyr576, Tyr577, and Tyr861, which are considered to be Src kinase substrates. This Src kinase–independent phosphorylation of FAK required an intact Src SH2 domain that mediates association of Src and FAK at peripheral adhesions. Use of a novel highly potent and selective Src kinase inhibitor AP23464 combined with experiments in Src/Fyn/Yes–deficient fibroblasts showed that increased phosphorylation of FAK in cells expressing SrcMF did not require Src-like kinases. However, specific phosphorylation on Tyr925 of FAK was not evident in SrcMF- or Src251-expressing cells, and lack of Src kinase–dependent phosphorylation on this site was associated with impaired adhesion turnover. Our data show that Src kinase activity is required for adhesion turnover associated with cell migration in cancer cells and that, in addition to the catalytic activity, Src also acts as an adaptor to recruit other kinases that can phosphorylate key substrates including FAK. These studies have implications for tumor progression with respect to the use of Src kinase inhibitors.
Expression and Nuclear Location of the Transcriptional Repressor Kaiso Is Regulated by the Tumor Microenvironment
Authors: Soubry Adelheid , van Hengel Jolanda , Parthoens Eef , Colpaert Cecile , Van Marck Eric , Waltregny David , Reynolds Albert B. , van Roy Frans 
Published: September 2005

Abstract
Kaiso is a BTB/POZ zinc finger protein originally described as an interaction partner of p120ctn. In cultured cell lines, Kaiso is found almost exclusively in the nucleus, where it generally acts as a transcriptional repressor. Here, we describe the first in situ immunolocalization studies of Kaiso expression in normal and cancerous tissues. Surprisingly, we found striking differences between its behavior in monolayers of different cell lines, three-dimensional cell culture systems, and in vivo. Although nuclear localization was sometimes observed in tissues, Kaiso was more often found in the cytoplasm, and in some cell types it was absent. In general, Kaiso and p120ctn did not colocalize in the nucleus. To examine this phenomenon more carefully, tumor cells exhibiting strong nuclear Kaiso staining in vitro were injected into nude mice and grown as xenografts. The latter showed a progressive translocation of Kaiso towards the cytoplasm over time, and even complete loss of expression, especially in the center of the tumor nodules. When xenografted tumors were returned to cell culture, Kaiso was re-expressed and was once again found in the nucleus. Translocation of Kaiso to the cytoplasm and down-regulation of its levels were also observed under particular experimental conditions in vitro, such as formation of spheroids and acini. These data strongly imply an unexpected influence of the microenvironment on Kaiso expression and localization. As transcriptional repression is a nuclear event, this phenomenon is likely a crucial factor in the regulation of Kaiso function.
Extensive Chromosomal Instability in Rad51d-Deficient Mouse Cells
Authors: Smiraldo Phillip G. , Gruver Aaron M. , Osborn Joshua C. , Pittman Douglas L. 
Published: September 2005

Abstract
Homologous recombination is a double-strand break repair pathway required for resistance to DNA damage and maintaining genomic integrity. In mitotically dividing vertebrate cells, the primary proteins involved in homologous recombination repair are RAD51 and the five RAD51 paralogs, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. In the absence of Rad51d, human and mouse cells fail to proliferate, and mice defective for Rad51d die before birth, likely as a result of genomic instability and p53 activation. Here, we report that a p53 deletion is sufficient to extend the life span of Rad51d-deficient embryos by up to 6 days and rescue the cell lethal phenotype. The Rad51d−/− Trp53−/− mouse embryo–derived fibroblasts were sensitive to DNA-damaging agents, particularly interstrand cross-links, and exhibited extensive chromosome instability including aneuploidy, chromosome fragments, deletions, and complex rearrangements. Additionally, loss of Rad51d resulted in increased centrosome fragmentation and reduced levels of radiation-induced RAD51-focus formation. Spontaneous frequencies of sister chromatid exchange were not affected by the absence of Rad51d, but sister chromatid exchange frequencies did fail to be induced upon challenge with the DNA cross-linking agent mitomycin C. These findings support a crucial role for mammalian RAD51D in normal development, recombination, and maintaining mammalian genome stability.
Epidermal Expression of the Translation Inhibitor Programmed Cell Death 4 Suppresses Tumorigenesis
Authors: Jansen Aaron P. , Camalier Corinne E. , Colburn Nancy H. 
Published: September 2005

Abstract
Programmed cell death 4 (Pdcd4) is a novel repressor of in vitro transformation. Pdcd4 directly inhibits the helicase activity of eukaryotic translation initiation factor 4A, a component of the translation initiation complex. To ascertain whether Pdcd4 suppresses tumor development in vivo, we have generated transgenic mice that overexpress Pdcd4 in the epidermis (K14-Pdcd4). K14-regulated Pdcd4 expression caused a neonatal short-hair phenotype due to early catagen entry compared with matched wild-type siblings. In response to the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis protocol, K14-Pdcd4 mice showed significant reductions in papilloma formation, carcinoma incidence, and papilloma-to-carcinoma conversion frequency compared with wild-type mice. The translational efficiency of an mRNA engineered to form a structured 5′ untranslated region (UTR) was attenuated in primary keratinocytes when Pdcd4 was overexpressed. Pdcd4 inhibited by 46% TPA-induced activator protein-1 (AP-1)–dependent transcription, an event required for tumorigenesis. CDK4 and ornithine decarboxylase (ODC) are candidates for Pdcd4-regulated translation as their mRNAs contain 5′structured UTRs. In K14-Pdcd4 primary keratinocytes expressing activated Ha-Ras to mimic DMBA-initiated epidermis, ODC and CDK4 protein levels were decreased by 40% and 46%, respectively. Expression of a protein encoded by 5′ unstructured mRNA showed no change. These results extend to an in vivo model the observations that Pdcd4 inhibits both translation initiation and AP-1 activation while decreasing benign tumor development and malignant progression. The K14-Pdcd4 mice seem to validate translation initiation as a novel target for cancer prevention.
p210BCR-ABL inhibits SDF-1 Chemotactic Response via Alteration of CXCR4 Signaling and Down-regulation of CXCR4 Expression
Authors: Geay Jean-Francois , Buet Dorothée , Zhang Yanyan , Foudi Adlen , Jarrier Peggy , Berthebaud Magali , Turhan Ali G. , Vainchenker William , Louache Fawzia 
Published: September 2005

Abstract
It has been shown that p210BCR-ABL significantly impairs CXCR4 signaling. We report here that the migratory response to SDF-1 was profoundly altered in blast crisis, whereas chronic-phase CD34+ cells migrated normally to this chemokine. This migratory defect was associated with a low CXCR4 membrane expression. In vitro STI-571 treatment of CD34+ cells from patients in blast crisis markedly increased the CXCR4 transcript and CXCR4 membrane expression. Because p210BCR-ABL frequently increases with disease progression, we determined the effects of high and low p210BCR-ABL expression on CXCR4 protein in the granulocyte macrophage colony-stimulating factor–dependent human cell line MO7e. p210BCR-ABL expression distinctly alters CXCR4 protein through two different mechanisms depending on its expression level. At low expression, a signaling defect was detected with no modification of CXCR4 expression. However, higher p210BCR-ABL expression induced a marked down-regulation of CXCR4 that is related to its decreased transcription. The effect of p210BCR-ABL required its tyrosine kinase activity. Collectively, these data indicate that p210BCR-ABL could affect CXCR4 by more than one mechanism and suggest that down-regulation of CXCR4 may have important implications in chronic myelogenous leukemia pathogenesis.
Role of Checkpoint Kinase 1 in Preventing Premature Mitosis in Response to Gemcitabine
Authors: Morgan Meredith A. , Parsels Leslie A. , Parsels Joshua D. , Mesiwala Alefiyah K. , Maybaum Jonathan , Lawrence Theodore S. 
Published: September 2005

Abstract
The deoxycytidine analogue 2′,2′-difluoro-2′-deoxycytidine (gemcitabine) is a potent radiation sensitizer in a variety of solid tumors and tumor cell lines. Previous studies have shown that radiosensitization by gemcitabine is accompanied by simultaneous depletion of dATP pools (through ribonucleotide reductase inhibition) and accumulation in the S-phase of the cell cycle. Because of the importance of cell cycle redistribution in gemcitabine-mediated radiosensitization, we investigated the role of checkpoint kinase (Chk) 1 and Chk2 in gemcitabine-induced cell cycle arrest. We hypothesized that gemcitabine might induce Chk1 or Chk2 signal transduction pathways that mediate S-phase arrest. We found that radiosensitizing concentrations of gemcitabine induced accumulation of phosphorylated Chk1 and Chk2 and down-regulation of Cdc25A in BxPC-3 (10 nmol/L), Panc-1 (100 nmol/L), A549 (30 nmol/L), RKO (30 nmol/L), and SW620 (30 nmol/L) cells. Depletion of Chk1 from Panc-1 cells prevented the down-regulation of Cdc25A in response to gemcitabine. Furthermore, Chk1 depletion permitted Panc-1 and SW620 cells treated with gemcitabine to enter mitosis despite incomplete DNA synthesis. However, depletion of neither Chk1 nor Chk2 abrogated the inhibition of DNA synthesis in response to gemcitabine. These results provide evidence that Chk1 negatively regulates entry into mitosis in response to gemcitabine. Furthermore, these data imply that Chk1 acts to coordinate the cell cycle with DNA synthesis, thus preventing premature mitotic entry in gemcitabine-treated cells.
Inactivation of Anthracyclines by Cellular Peroxidase
Authors: Reszka Krzysztof J. , Wagner Brett A. , Teesch Lynn M. , Britigan Bradley E. , Spitz Douglas R. , Burns C. Patrick 
Published: September 2005

Abstract
The anticancer anthracyclines, doxorubicin and daunorubicin, are highly cytotoxic to both cancer and normal cells. In this work, we have investigated the capacity of cellular myeloperoxidase to inactivate these agents. We show that incubation of human leukemia HL-60 cells with the anthracyclines in the presence of hydrogen peroxide and nitrite causes irreversible oxidation of the drugs, suggesting an extensive modification of their chromophores. Methimazole, 4-aminobenzoic acid hydrazide, or azide inhibits the reaction, suggesting that it is mediated by the cellular myeloperoxidase, an enzyme naturally present in large amounts in HL-60 cells. In contrast to the intact drugs, the oxidatively transformed anthracyclines were substantially less cytotoxic for HL-60 (assayed by apoptosis) and PC3 prostate cancer cells and H9c2 rat cardiac myoblasts in vitro (assayed by clonogenic survival), indicating that the oxidative metabolism of these agents leads to their inactivation. Using tandem mass spectrometry, we identified two specific metabolic products of the anthracycline degradation, 3-methoxyphthalic acid and 3-methoxysalicylic acid. These two metabolic products were obtained as authentic compounds and were nontoxic to HL-60 leukemic cells and cardiac myocytes. These findings may have important implications for the cellular pharmacology of anthracyclines and for clinical oncology.
Human High Molecular Weight Melanoma-Associated Antigen Mimicry by Mouse Anti-Idiotypic Monoclonal Antibody MK2-23: Enhancement of Immunogenicity of Anti-Idiotypic Monoclonal Antibody MK2-23 by Fusion with Interleukin 2
Authors: Wang Xinhui , Ko Eric C. , Peng Liaomin , Gillies Stephen D. , Ferrone Soldano 
Published: September 2005

Abstract
To overcome unresponsiveness to the self-high molecular weight melanoma-associated antigen (HMW-MAA) in hosts with constitutive HMW-MAA expression, we have used as immunogen the anti-idiotypic monoclonal antibody (mAb) MK2-23, which mimics the antigenic determinant recognized by the anti-HMW-MAA mAb 763.74. In a phase I/II clinical trial, anti-idiotypic mAb MK2-23, conjugated to keyhole limpet hemocyanin (KLH) as a carrier and given with Bacillus Calmette-Guerin (BCG) as an adjuvant, elicited HMW-MAA-specific antibodies in about 60% of the immunized melanoma patients. The immune response was associated with survival prolongation. However, safety and standardization issues associated with the use of KLH and BCG in the clinical setting have prompted us to develop alternative immunization strategies. Conjugation of human interleukin 2 (IL-2) to mAb MK2-23 variable regions covalently linked to human immunoglobulin constant regions enhanced mAb MK2-23 immunogenicity in BALB/c mice to an extent similar to that induced by mAb MK2-23 conjugated to KLH and given with Freund's adjuvant. As determined by the level of serum antibodies and delayed-type hypersensitivity responses to HMW-MAA-bearing melanoma cells, immunization of mice with the MK2-23-IL-2 fusion protein elicited more robust humoral and cellular responses, respectively, than immunization with KLH-conjugated mAb MK2-23 and separate administration of IL-2. The immunogenicity of the fusion protein is dependent on IL-2 conjugation, because immunization of mice with either mAb MK2-23 or chimeric mAb MK2-23, in combination with IL-2, was not as effective in eliciting HMW-MAA-specific immune responses. These results suggest that the MK2-23-IL-2 fusion protein represents a useful immunogen to implement active specific immunotherapy in patients with melanoma, because it bypasses the requirement for KLH conjugation and adjuvant administration.
ErbB2 Promotes Src Synthesis and Stability: Novel Mechanisms of Src Activation That Confer Breast Cancer Metastasis
Authors: Tan Ming , Li Ping , Klos Kristine S. , Lu Jing , Lan Keng-Hsueh , Nagata Yoichi , Fang Dexing , Jing Tong , Yu Dihua 
Published: September 2005

Abstract
Activation of Src kinase plays important roles in the development of many neoplasias. Most of the previous Src studies focused on the deregulation of Src kinase activity. The deregulated Src protein synthesis and stability in mediating malignant phenotypes of cancer cells, however, have been neglected. While investigating the signal transduction pathways contributing to ErbB2-mediated metastasis, we found that ErbB2-activated breast cancer cells that had higher metastatic potentials also had increased Src activity compared with ErbB2 low-expressing cells. The increased Src activity in ErbB2-activated cells paralleled higher Src protein levels, whereas Src RNA levels were not significantly altered. Our studies revealed two novel mechanisms that are involved in Src protein up-regulation and activation by ErbB2: (a) ErbB2 increased Src translation through activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway and (b) ErbB2 increased Src stability most likely through the inhibition of the calpain protease. Furthermore, inhibition of Src activity by a Src-specific inhibitor, PP2, or a Src dominant-negative mutant dramatically reduced ErbB2-mediated cancer cell invasion in vitro and metastasis in an experimental metastasis animal model. Together, activation of ErbB2 and downstream signaling pathways can lead to increased Src protein synthesis and decreased Src protein degradation resulting in Src up-regulation and activation, which play critical roles in ErbB2-mediated breast cancer invasion and metastasis.
Altered Gene Expression Patterns in MCF-7 Cells Induced by the Urban Dust Particulate Complex Mixture Standard Reference Material 1649a
Authors: Mahadevan Brinda , Keshava Channa , Musafia-Jeknic Tamara , Pecaj Arta , Weston Ainsley , Baird William M. 
Published: September 2005

Abstract
Human exposures to polycyclic aromatic hydrocarbon (PAH) occur in complex mixtures. Here, gene expression patterns were investigated using standard reference material (SRM) 1649a (urban dust). MCF-7 cells were exposed to SRM 1649a alone or SRM 1649a with either benzo[a]pyrene (BP) or dibenzo[a,l]pyrene (DBP) for 24 hours. Global analyses of the gene expression data revealed alterations of 41 RNA transcripts with at least 2-fold change (signal log ratio ≤ −1 or ≥ 1) in response to SRM 1649a exposure. Increase in expression of cytochrome P450 (CYP) genes was observed in response to BP exposure (CYP1A1 and CYP1B1; signal log ratio of 4.7 and 2.5, respectively). An additive induction of CYP1A1 and CYP1B1 was observed with cotreatment of SRM 1649a and BP. On the contrary, no change in gene expression of CYP1A1 and CYP1B1 was observed when the cells were exposed to DBP. Furthermore, to study the effect of complex PAH mixtures on the metabolic activation of carcinogenic PAH to DNA-binding derivatives and to relate this with gene expression studies, PAH-DNA adduct formation was determined. SRM 1649a decreased the total level of BP-DNA adducts in comparison with BP alone. No significant difference in adduct levels was observed in response to either DBP alone or in combination with SRM 1649a. These results provide a transcriptional signature for chemical carcinogen exposure; in addition, they suggest a major factor in carcinogenic activity of PAH within complex mixtures is their ability to promote or inhibit the activation of carcinogenic PAH by the induction of CYP enzymes.