bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Novel DNA Binding Site and a Transcriptional Target for Activating Transcription Factor 5 in C6 Glioma and MCF-7 Breast Cancer Cells
Authors: Li Guangfu , Li Wenhong , Angelastro James M. , Greene Lloyd A. , Liu David X. 
Published: June 2009

Abstract
Recent reports indicate that the activating transcription factor 5 (ATF5) is required for the survival of cancer cells but not for noncancer cells. However, the mechanisms by which ATF5 regulates genes and promotes cell survival are not clear. Using a cyclic amplification and selection of targets (CASTing) approach, we identified a novel ATF5 consensus DNA binding sequence. We show in C6 glioma and MCF-7 breast cancer cells that ATF5 occupies this sequence and that ATF5 activates reporter gene expression driven by this site. Conversely, reporter activity is diminished when ATF5 activity is blocked or when ATF5 expression is down-regulated by serum withdrawal. We further show that early growth response factor 1 (Egr-1), whose promoter contains two adjacent ATF5 consensus binding sites at a conserved promoter position in rat, mouse, and human, is targeted and regulated by ATF5 in C6 and MCF-7 cells. These data provide new insight on the mechanisms by which ATF5 promotes gene regulation and cancer-specific cell survival. (Mol Cancer Res 2009;7(6):933–43)
Down-Regulation of 3-Phosphoinositide–Dependent Protein Kinase-1 Levels Inhibits Migration and Experimental Metastasis of Human Breast Cancer Cells
Authors: Liu Ying , Wang Jingna , Wu Min , Wan Wuzhou , Sun Ronghua , Yang De , Sun Xiangjun , Ma Dalong , Ying Guoguang , Zhang Ning 
Published: June 2009

Abstract
High expression of 3-phosphoinositide–dependent protein kinase-1 (PDK1) has been detected in various invasive cancers. In the current study, we investigated its role in cancer cell migration and experimental metastasis. Down-regulation of PDK1 expression by small interference RNA markedly inhibited spontaneous migration and epidermal growth factor (EGF)–induced chemotaxis of human breast cancer cells. The defects were rescued by expressing wild-type PDK1. PDK1-depleted cells showed impaired EGF-induced actin polymerization and adhesion, probably due to a decrease in phosphorylation of LIM kinase/cofilin and integrin β1. Confocal microscopy revealed that EGF induced cotranslocation of PDK1 with Akt and protein kinase Cζ (PKCζ), regulators of LIM kinase, and integrin β1. Furthermore, PDK1 depletion dampened EGF-induced phosphorylation and translocation of Akt and PKCζ, suggesting that Akt and PKCζ functioned downstream of PDK1 in the chemotactic signaling pathway. In severe combined immunodeficiency mice, PDK1-depleted human breast cancer cells formed more slowly growing tumors and were defective in extravasation to mouse lungs after i.v. injection. Our results indicate that PDK1 plays an important role in regulating the malignant behavior of breast cancer cells, including their motility, through activation of Akt and PKCζ. Thus, PDK1, which increases its expression in cancer cells, can be used as a target for the development of novel therapies. (Mol Cancer Res 2009;7(6):944–54)
Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration
Authors: Nguyen Alana H.T. , Béland Mélanie , Gaitan Yaned , Bouchard Maxime 
Published: June 2009

Abstract
Current therapeutic strategies against Wilms' tumor (WT) reach 80% to 85% success rate. In spite of this, a remaining 15% to 20% of tumors relapse and are associated with increased metastasis and poor prognosis. To identify new regulators of WT progression, we screened for developmental target genes of Pax2, a key regulator of kidney development and a WT signature gene. We show that one of these target genes, calcineurin A–binding protein (CnABP), is coexpressed with Pax2 during kidney development and is overexpressed in &gt;70% of WT samples analyzed. The CnABP gene encodes a novel protein product conserved in higher vertebrates. We show that CnABP promotes cell proliferation and migration in cell culture experiments. Biochemical analyses additionally identified an interaction between CnABP and calcineurin Aβ, the catalytic subunit of the calcium-responsive serine/threonine phosphatase calcineurin. We show that this interaction leads to the inhibition of calcineurin phosphatase activity and prevents nuclear factor of activated T-cell (NFAT) nuclear translocation. Inhibition of NFAT nuclear localization results in decreased NFAT transcriptional response. Together, these data identify a new modulator of calcineurin signaling up-regulated in WTs. (Mol Cancer Res 2009;7(6):821–31)
Effects of Raf Kinase Inhibitor Protein Expression on Metastasis and Progression of Human Breast Cancer
Authors: Li Hong Zhao , Gao Yan , Zhao Xiu Lan , Liu Yi Xin , Sun Bao Cun , Yang Jie , Yao Zhi 
Published: June 2009

Abstract
Raf kinase inhibitor protein (RKIP) has been shown to be a metastasis suppressor in many kinds of malignant tumors. But its function in breast cancer was not yet clarified completely. We detected RKIP expression in clinical samples of primary breast cancer, breast cancer metastases, and in different breast cancer cells. Compared with the normal breast epithelia, benign breast epithelia, or in situ ductal carcinoma, the expression level of RKIP is decreased in invasive carcinoma and significantly reduced or lost in the metastasis lymph node matched to the invasive carcinoma. To explore the potential role of RKIP in breast cancer metastasis, we studied the effect of RKIP on the malignant phenotypes of the breast cancer cells with ectopically overexpression or knockdown of RKIP. Cell proliferation, soft-agar colony formation, in vitro adhesion assay, invasion, and migation assays were done to examine the malignant phenotypes of the transfected cells. Consequently, RKIP has no effect on in vitro proliferation rate or colony-forming ability of MDA-MB-435 cells. In vitro cell invasion and migration assays indicated that the RKIP expression was inversely associated with the invasiveness of MDA-MB-435 cells. Consistent with these results, in the orthotopic murine models, we observed that overexpression of RKIP in breast cancer cells impaired invasiveness and metastasis, whereas down-regulation of RKIP expression promoted invasiveness and metastasis. These results indicate that RKIP is a metastasis suppressor gene of human breast cancer. (Mol Cancer Res 2009;7(6):832–40)
Ceramide Regulates Gemcitabine-Induced Senescence and Apoptosis in Human Pancreatic Cancer Cell Lines
Authors: Modrak David E. , Leon Evelyn , Goldenberg David M. , Gold David V. 
Published: June 2009

Abstract
Bioactive sphingolipids are potent intracellular signaling molecules having profound effects on cell death, growth, and differentiation. Pharmacologic manipulation of sphingolipid levels could have a significant effect on the induction of apoptosis by anticancer agents, and thus, improve treatment efficacy. We observed that gemcitabine cannot completely kill AsPc1 and Panc1 human pancreatic cancer cells in culture; even at high concentrations of gemcitabine, 30% to 40% of the cells remain viable. By adding sphingomyelin to the culture medium, gemcitabine-induced cell death increased synergistically to &gt;90%. Panc1 cells that survived high concentrations of gemcitabine had an increase in β-galactosidase activity, a marker of senescence. The inclusion of sphingomyelin with gemcitabine reduced β-galactosidase activity, as compared with cells treated with gemcitabine alone. Expression of p21waf1/cip1 in both cell lines exposed to sphingomyelin, gemcitabine, and gemcitabine + sphingomyelin varied relative to the untreated group. C8-ceramide induced both cell death and senescence in a dose-dependent manner. These results indicate that gemcitabine induces senescence in pancreatic cancer cells and that sphingomyelin-enhanced chemosensitivity is achieved through reducing the induction of senescence by redirecting the cell to enter the apoptotic pathway. Ceramide levels seem to be critical to this decision, with cell cycle progression being uninhibited at low ceramide levels, senescence induced at moderate levels, and apoptosis initiated at high levels. Our results provide further evidence that targeting the sphingolipid metabolism is a means of enhancing the efficacy of chemotherapeutic agents. (Mol Cancer Res 2009;7(6):890–6)
Zebrafish Hagoromo Mutants Up-Regulate fgf8 Postembryonically and Develop Neuroblastoma
Authors: Amsterdam Adam , Lai Kevin , Komisarczuk Anna Z. , Becker Thomas S. , Bronson Roderick T. , Hopkins Nancy , Lees Jacqueline A. 
Published: June 2009

Abstract
We screened an existing collection of zebrafish insertional mutants for cancer susceptibility by histologic examination of heterozygotes at 2 years of age. As most mutants had no altered cancer predisposition, this provided the first comprehensive description of spontaneous tumor spectrum and frequency in adult zebrafish. Moreover, the screen identified four lines, each carrying a different dominant mutant allele of Hagoromo previously linked to adult pigmentation defects, which develop tumors with high penetrance and that histologically resemble neuroblastoma. These tumors are clearly neural in origin, although they do not express catecholaminergic neuronal markers characteristic of human neuroblastoma. The zebrafish tumors result from inappropriate maintenance of a cell population within the cranial ganglia that are likely neural precursors. These neoplasias typically remain small but they can become highly aggressive, initially traveling along cranial nerves, and ultimately filling the head. The developmental origin of these tumors is highly reminiscent of human neuroblastoma. The four mutant Hagoromo alleles all contain viral insertions in the fbxw4 gene, which encodes an F-box WD40 domain–containing protein. However, although one allele clearly reduced the levels of fbxw4 mRNA, the other three insertions had no detectable effect on fbw4 expression. Instead, we showed that all four mutations result in the postembryonic up-regulation of the neighboring gene, fibroblast growth factor 8 (fgf8). Moreover, fgf8 is highly expressed in the tumorigenic lesions. Although fgf8 overexpression is known to be associated with breast and prostate cancer in mammals, this study provides the first evidence that fgf8 misregulation can lead to neural tumors. (Mol Cancer Res 2009;7(6):841–50)
CD151 Regulates Tumorigenesis by Modulating the Communication between Tumor Cells and Endothelium
Authors: Sadej Rafal , Romanska Hanna , Baldwin Gouri , Gkirtzimanaki Katerina , Novitskaya Vera , Filer Andrew D. , Krcova Zuzana , Kusinska Renata , Ehrmann Jiri , Buckley Christopher D. , Kordek Radzisław , Potemski Piotr , Eliopoulos Aristides G. , Lalani El-Nasir , Berditchevski Fedor 
Published: June 2009

Abstract
The tetraspanin CD151 forms stoichiometric complexes with laminin-binding integrins (e.g., α3β1, α6β1, and α6β4) and regulates their ligand-binding and signaling functions. We have found that high expression of CD151 in breast cancers is associated with decreased overall survival (3.44-fold higher risk of death). Five-year estimated survival rates were 45.8% (95% confidence interval, 16.4-71.4%) for CD151-positive patients and 79.9% (95% confidence interval, 62.2-90.0%) for CD151-negative patients. Furthermore, CD151 was positively associated with axillary lymph node involvement. To study the biological significance of this observation, we investigated the contribution of CD151 in breast cancer tumorigenesis using MDA-MB-231 cells as a model system. Stable down-regulation of this tetraspanin by short-hairpin RNA decreased the tumorigenicity of these cells in mice. Detailed immunohistologic analysis of CD151(+) and CD151(−) xenografts showed differences in tumor vascular pattern. Vascularization observed at the subcutaneous border of the CD151(+) tumors was less pronounced or absent in the CD151(−) xenografts. In vitro experiments have established that depletion of CD151 did not affect the inherent proliferative capacity of breast cancer cells in three-dimensional extracellular matrices, but modified their responses to endothelial cells in coculture experiments. The modulatory activity of CD151 was dependent on its association with both α3β1 and α6β4 integrins. These data point to a new role of CD151 in tumorigenesis, whereby it functions as an important regulator of communication between tumor cells and endothelial cells. These results also identify CD151 as a potentially novel prognostic marker and target for therapy in breast cancer. (Mol Cancer Res 2009;7(6):787–98)
Thiacremonone Augments Chemotherapeutic Agent–Induced Growth Inhibition in Human Colon Cancer Cells through Inactivation of Nuclear Factor-κB
Authors: Ban Jung Ok , Lee Hee Soon , Jeong Heon-Sang , Song Sugkil , Hwang Bang Yeon , Moon Dong Cheul , Yoon Do Young , Han Sang Bae , Hong Jin Tae 
Published: June 2009

Abstract
Chemotherapeutic strategies commonly use multiple agents to overcome drug resistance and to lower drug toxicity. Activation of nuclear factor-κB (NF-κB) is implicated in drug resistance in cancer cells. Previously, we reported that thiacremonone, a novel sulfur compound isolated from garlic, inhibited NF-κB and cancer cell growth with IC50 values about 100 μg/mL in colon cancer cells. In the present study, we tested whether thiacremonone could increase susceptibility of cancer cells to chemotherapeutics through inactivation of NF-κB. Colon cancer cells were cotreated with thiacremonone (50 μg/mL, half dose of IC50) and lower doses of each chemotherapeutic agent (half dose of IC50) for 24 hours. NF-κB activity was completely abrogated in cells treated with a combination of thiacremonone and docetaxel, whereas thiacremonone on its own did not alter NF-κB activity. This combined drug effect was also found with other anticancer drugs in colon cancer and in other cancer cells. In good correlation with inhibition of cell growth and NF-κB activity, the combination treatment also regulated NF-κB target genes. Oral treatment of mice with thiacremonone (1 mg/kg) by administering it in drinking water for 4 weeks significantly augmented docetaxel (1 mg/kg, i.p., four times)–induced decrease of tumor growth accompanied with regulation of NF-κB activity and NF-κB target genes. These results warrant carefully designed clinical studies investigating the combination of thiacremonone and commonly used chemotherapeutic agents for the treatment of human cancers. (Mol Cancer Res 2009;7(6):870–9)
Study of Regional-Scale Boundary Layer Characteristics over Northern India with a Special Reference to the Role of the Thar Desert in Regional-Scale Transport
Authors: Panda Jagabandhu , Sharan Maithili , Gopalakrishnan S. G. 
Published: June 2009

AbstractExtensive contrasts of land surface heterogeneities have a pivotal role in modulating boundary layer processes and consequently, the regional-scale dispersion of air pollutants. The Weather Research and Forecasting (WRF) modeling system has been used to analyze the regional-scale boundary layer features over northern India. Two cases, 9–11 December 2004 and 20–22 May 2005, representing the winter and summer season, respectively, are chosen for the simulations. The model results have been compared with the observations from the India Meteorological Department (IMD) and Wyoming Weather Web data archive over three cities: Delhi, Ahmedabad, and Jodhpur. The simulations show that the thermal stratifications and the associated wind pattern are very well supported by land surface characteristics over the region. The results signify that the underlying land surface along with the prevailing hemispheric-scale meteorological processes (synoptic conditions) is the driver of the simulated patterns. The study implies that thermally driven regional circulations play a major role in the transport of particulate matter from the Thar Desert to Delhi and its neighboring regions during summer.
Reexamining the Vertical Structure of Tangential Winds in Tropical Cyclones: Observations and Theory
Authors: Stern Daniel P. , Nolan David S. 
Published: June 2009

Abstract
A few commonly held beliefs regarding the vertical structure of tropical cyclones drawn from prior studies, both observational and theoretical, are examined in this study. One of these beliefs is that the outward slope of the radius of maximum winds (RMW) is a function of the size of the RMW. Another belief is that the outward slope of the RMW is also a function of the intensity of the storm. Specifically, Shea and Gray found that the RMW becomes increasingly vertical with increasing intensity and decreasing radius. The third belief evaluated here is that the RMW is a surface of constant absolute angular momentum M. These three conventional wisdoms of vertical structure are revisited with a dataset of three-dimensional Doppler wind analyses, comprising seven hurricanes on 17 different days. Azimuthal mean tangential winds are calculated for each storm, and the slopes of the RMW and M surfaces are objectively determined. The outward slope of the RMW is shown to increase with radius, which supports prior studies. In contrast to prior results, no relationship is found between the slope of the RMW and intensity. It is shown that the RMW is indeed closely approximated by an M surface for the majority of storms. However, there is a small but systematic tendency for M to decrease upward along the RMW. Utilizing Emanuel’s analytical hurricane model, a new equation is derived for the slope of the RMW in radius–pressure space. This predicts a linear increase of slope with radius and essentially no dependence of slope on intensity. An exactly analogous equation can be derived in log-pressure height coordinates, and a numerical solution yields the same conclusions in geometric height coordinates. These conclusions are further supported by the results of simulations utilizing Emanuel’s simple, time-dependent, axisymmetric hurricane model. As both the model and the analytical theory are governed by the dual constraints of thermal wind balance and slantwise moist neutrality, it is demonstrated that it is these two assumptions that require the slope of the RMW to be a function of its size but not of the intensity of the storm. Finally, it is shown that within the context of Emanuel’s theory, the RMW must very closely approximate an M surface through most of the depth of the vortex.
Rapid Development of the Tropical Cyclone Warm Core
Authors: Vigh Jonathan L. , Schubert Wayne H. 
Published: June 2009

Abstract
This paper presents a simple theoretical argument to isolate the conditions under which a tropical cyclone can rapidly develop a warm-core thermal structure and subsequently approach a steady state. The theoretical argument is based on the balanced vortex model and, in particular, on the associated transverse circulation equation and the geopotential tendency equation. These second-order partial differential equations contain the diabatic forcing and three spatially varying coefficients: the static stability A, the baroclinity B, and the inertial stability C. Thus, the transverse circulation and the temperature tendency in a tropical vortex depend not only on the diabatic forcing but also on the spatial distributions of A, B, and C. Experience shows that the large radial variations of C are typically the most important effect. Under certain simplifying assumptions as to the vertical structure of the diabatic forcing and the spatial variability of A, B, and C, the transverse circulation equation and the geopotential tendency equation can be solved via separation of variables. The resulting radial structure equations retain the dynamically important radial variation of C and can be solved in terms of Green’s functions. These analytical solutions show that the vortex response to a delta function in the diabatic heating depends critically on whether the heating occurs in the low-inertial-stability region outside the radius of maximum wind or in the high-inertial-stability region inside the radius of maximum wind. This result suggests that rapid intensification is favored for storms that have at least some of the eyewall convection inside the radius of maximum wind. The development of an eye partially removes diabatic heating from the high-inertial-stability region of the storm center; however, rapid intensification may continue if the eyewall heating continues to become more efficient. As the warm core matures and static stability increases over the inner core, conditions there become less favorable for deep upright convection and the storm tends to approach a steady state.
Interannual Variability of the Cyclonic Activity along the U.S. Pacific Coast: Influences on the Characteristics of Winter Precipitation in the Western United States
Authors: Myoung Boksoon , Deng Yi 
Published: June 2009

Abstract
This study examines the observed interannual variability of the cyclonic activity along the U.S. Pacific coast and quantifies its impact on the characteristics of both the winter total and extreme precipitation in the western United States. A cyclonic activity function (CAF) was derived from a dataset of objectively identified cyclone tracks in 27 winters (1979/80–2005/06). The leading empirical orthogonal function (EOF1) of the CAF was found to be responsible for the EOF1 of the winter precipitation in the western United States, which is a monopole mode centered over the Pacific Northwest and northern California. On the other hand, the EOF2 of the CAF contributes to the EOF2 of the winter precipitation, which indicates that above-normal precipitation in the Pacific Northwest and its immediate inland regions tends to be accompanied by below-normal precipitation in California and the southwestern United States and vice versa. The first two EOFs of CAF (precipitation) account for about 70% (78%) of the total interannual variance of CAF (precipitation). The second EOF modes of both the CAF and precipitation are significantly linked to the ENSO signal on interannual time scales. A composite analysis further reveals that the leading CAF modes increase (decrease) the winter total precipitation by increasing (decreasing) both the number of rainy days per winter and the extremeness of precipitation. The latter was quantified in terms of the 95th percentile of the daily rain rate and the probability of precipitation being heavy given a rainy day. The implications of the leading CAF modes for the water resources and the occurrence of extreme hydrologic events in the western United States, as well as their dynamical linkages to the Pacific storm track and various atmospheric low-frequency modes (i.e., teleconnection patterns), are also discussed.