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1.
Phys Rev Lett ; 126(16): 167001, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33961453

RESUMO

The presence of a small concentration of in-plane Fe dopants in La_{1.87}Sr_{0.13}Cu_{0.99}Fe_{0.01}O_{4} is known to enhance stripelike spin and charge density wave (SDW and CDW) order and suppress the superconducting T_{c}. Here, we show that it also induces highly two-dimensional superconducting correlations that have been argued to be the signatures of a new form of superconducting order, the so-called pair density wave (PDW) order. In addition, using resonant soft x-ray scattering, we find that the two-dimensional superconducting fluctuation is strongly associated with the CDW stripe. In particular, the PDW signature first appears when the correlation length of the CDW stripe grows over eight times the lattice unit (∼8a). These results provide critical conditions for the formation of the PDW order.

2.
J Hum Nutr Diet ; 34(2): 334-344, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33089908

RESUMO

BACKGROUND: Multiple studies have uncovered the effects that ingested fat has on human blood levels of testosterone. Yet, few reports have discussed the effect of circulating serum free fatty acids (FFAs). The present study aimed to explore the relationship between serum free fatty acids and blood levels of testosterone. METHODS: In total, 5719 adults were pooled from the database of the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2012. Based on multivariable-linear regression models, we employed a total of 30 FFAs to interpret the relationship of FFAs with blood levels of testosterone. Two models with covariate adjustments were designated for further evaluation and analysis. RESULTS: Capric acid [ß = -0.014, 95% confidence interval (CI) = -0.023, -0.004, P = 0.005], myristic acid (ß = -0.001, 95% CI = -0.001, 0.000, P ≤ 0.001), pentadecanoic acid (ß = -0.013, 95% CI = -0.018, -0.008, P ≤ 0.001), margaric acid (ß = -0.011, 95% CI = -0.017, -0.005, P ≤ 0.001) and alpha-linolenic acid (ß = -0.001, 95% CI = -0.002, 0.000, P = 0.004) in the fully adjusted model were significantly negatively correlated with the testosterone level inh obese men. In the fully adjusted model for the female analysis, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, myristoleic acid, oleic acid, nervonic acid and alpha-linolenic acid were found significantly associated with the testosterone level. CONCLUSIONS: Our findings indicate a significant negative correlation between serum FFAs and blood levels of testosterone. Furthermore, we reveal the essentiality of serum FFAs and their potential effects on the reduction of testosterone levels.


Assuntos
Ácidos Graxos não Esterificados , Testosterona , Adulto , Ácidos Graxos , Feminino , Humanos , Masculino , Inquéritos Nutricionais , Ácido Oleico , Ácido Palmítico
3.
Osteoporos Int ; 31(7): 1361-1367, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32170395

RESUMO

Loss of bone mineral density and skeletal muscle area are linked in lung transplant patients. This loss is greater in patients with restrictive compared with obstructive lung diseases. INTRODUCTION: Sarcopenia and osteoporosis are associated with aging and chronic illnesses and may be linked in patients with advanced lung disease. Pectoralis muscle index (PMI) quantitated on computed tomography (CT) of the chest can be used to measure skeletal muscle mass. This study aimed to determine the relationship of PMI to clinical parameters including bone mineral density (BMD) in candidates for lung transplantation. METHODS: A retrospective review of transplant candidates at a single center was performed. Demographic, anthropomorphic, and clinical data were recorded. Pectoralis muscle area (PMA) was determined on an axial slice from a chest CT. PMI was calculated as the PMA divided by height squared. BMD was obtained from routine dual-energy X-ray absorptiometry (DXA) scan. RESULTS: In 226 included patients, mean PMI was 8.2 ± 3.0 cm2/m2 in males and 6.1 ± 2.1 cm2/m2 in females. Osteopenia was present in 44.4%, and 23.2% of patients had osteoporosis. Patients with obstructive lung disease had lower body mass index (22.0 ± 4.9 versus 27.9 ± 4.9 kg/m2, p < 0.001), PMI (6.0 ± 2.3 versus 8.2 ± 2.8 cm2/m2, p < 0.001), and BMD (- 2.3 ± 1.1 versus - 1.3 ± 1.1, p < 0.001) compared with patients with restrictive lung disease. PMI was a significant predictor of BMD (ß = 0.16, p < 0.001). CONCLUSION: The association between muscle area and BMD in lung transplant candidates suggests that similar mechanisms may underlie the development of both. Differences in PMI and BMD in patients with obstructive versus restrictive lung disease may result from differences in respiratory physiology or disease processes.


Assuntos
Densidade Óssea , Transplante de Pulmão , Absorciometria de Fóton , Feminino , Humanos , Pulmão , Transplante de Pulmão/efeitos adversos , Masculino , Músculos Peitorais/diagnóstico por imagem , Fenômenos Fisiológicos Respiratórios , Estudos Retrospectivos
4.
Proc Natl Acad Sci U S A ; 113(51): 14645-14650, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27930313

RESUMO

The existence of charge-density-wave (CDW) correlations in cuprate superconductors has now been established. However, the nature of the CDW ground state has remained uncertain because disorder and the presence of superconductivity typically limit the CDW correlation lengths to only a dozen unit cells or less. Here we explore the field-induced 3D CDW correlations in extremely pure detwinned crystals of YBa2Cu3O2 (YBCO) ortho-II and ortho-VIII at magnetic fields in excess of the resistive upper critical field ([Formula: see text]) where superconductivity is heavily suppressed. We observe that the 3D CDW is unidirectional and possesses a long in-plane correlation length as well as significant correlations between neighboring CuO2 planes. It is significant that we observe only a single sharply defined transition at a critical field proportional to [Formula: see text], given that the field range used in this investigation overlaps with other high-field experiments including quantum oscillation measurements. The correlation volume is at least two to three orders of magnitude larger than that of the zero-field CDW. This is by far the largest CDW correlation volume observed in any cuprate crystal and so is presumably representative of the high-field ground state of an "ideal" disorder-free cuprate.

5.
Phys Rev Lett ; 117(21): 216404, 2016 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-27911536

RESUMO

Half-filled electron systems, even with the maximized spin angular moment, have been given little attention because of their zero-orbital angular moment according to Hund's rule. Nevertheless, there are several measurements that show evidence of a nonzero orbital moment as well as spin-orbit coupling. Here we report for the first time the orbital order in a half-filled 4f-electron system GdB_{4}, using the resonant soft x-ray scattering at Gd M_{4,5}-edges. Furthermore, we discovered that the development of this orbital order is strongly coupled with the antiferromagnetic spin order. These results clearly demonstrate that even in half-filled electron systems the orbital angular moment can be an important parameter to describe material properties, and may provide significant opportunities for tailoring new correlated electron systems.

6.
Virus Genes ; 51(1): 1-11, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25895103

RESUMO

The Hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp), nonstructural protein 5B (NS5B), is anchored in the membrane through a C-terminal helix. A sequence of ca. 12 residues that connects the catalytically competent portion of the RdRp and the C-terminal helix, the juxtamembrane sequence (JMS), has a poorly defined role in RdRp function in a large part since it is translated from a cis-acting RNA element (CRE) that is essential for HCV replication. Using a HCV replicon that transposed a second copy of CRE to the 3' UTR of the HCV replicon, we demonstrate that amino acid substitutions in the JMS were detrimental for HCV replicon replication. Substitutions in the JMS also resulted in a defect in de novo-initiated RNAs synthesis in vitro and in a cell-based reporter assay. A nonnucleoside inhibitor of the NS5B that binds to the catalytic pocket was less potent in inhibiting NS5B in the presence of JMS mutations. The JMS mutants exhibit reduced stability in thermodenaturation assays, suggesting that the JMS helps confer a more stable conformation to NS5B that could impact RNA synthesis.


Assuntos
Inibidores Enzimáticos/metabolismo , Hepacivirus/enzimologia , RNA Viral/biossíntese , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Substituição de Aminoácidos , Linhagem Celular , Hepacivirus/genética , Temperatura Alta , Humanos , Modelos Moleculares , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Conformação Proteica , Estabilidade Proteica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética
7.
Nat Mater ; 12(8): 703-6, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23727948

RESUMO

A number of recent transport and magnetization studies have shown signs of ferromagnetism in the LaAlO3/SrTiO3 heterostructure, an unexpected property with no bulk analogue in the constituent materials. However, no experiment thus far has provided direct information on the host of the magnetism. Here we report spectroscopic investigations of the magnetism using element-specific techniques, including X-ray magnetic circular dichroism and X-ray absorption spectroscopy, along with corresponding model calculations. We find direct evidence for in-plane ferromagnetic order at the interface, with Ti(3+) character in the dxy orbital of the anisotropic t2g band. These findings establish a striking example of emergent phenomena at oxide interfaces.

8.
Nat Commun ; 14(1): 733, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36759612

RESUMO

Superconductivity in the cuprates is found to be intertwined with charge and spin density waves. Determining the interactions between the different types of order is crucial for understanding these important materials. Here, we elucidate the role of the charge density wave (CDW) in the prototypical cuprate La1.885Sr0.115CuO4, by studying the effects of large magnetic fields (H) up to 24 Tesla. At low temperatures (T), the observed CDW peaks reveal two distinct regions in the material: a majority phase with short-range CDW coexisting with superconductivity, and a minority phase with longer-range CDW coexisting with static spin density wave (SDW). With increasing magnetic field, the CDW first grows smoothly in a manner similar to the SDW. However, at high fields we discover a sudden increase in the CDW amplitude upon entering the vortex-liquid state. Our results signify strong coupling of the CDW to mobile superconducting vortices and link enhanced CDW amplitude with local superconducting pairing across the H - T phase diagram.

9.
J Virol ; 84(12): 5923-35, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20375156

RESUMO

The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) has been proposed to change conformations in association with RNA synthesis and to interact with cellular proteins. In vitro, the RdRp can initiate de novo from the ends of single-stranded RNA or extend a primed RNA template. The interactions between the Delta1 loop and thumb domain in NS5B are required for de novo initiation, although it is unclear whether these interactions are within an NS5B monomer or are part of a higher-order NS5B oligomeric complex. This work seeks to address how polymerase conformation and/or oligomerization affects de novo initiation. We have shown that an increasing enzyme concentration increases de novo initiation by the genotype 1b and 2a RdRps while primer extension reactions are not affected or inhibited under similar conditions. Initiation-defective mutants of the HCV polymerase can increase de novo initiation by the wild-type (WT) polymerase. GTP was also found to stimulate de novo initiation. Our results support a model in which the de novo initiation-competent conformation of the RdRp is stimulated by oligomeric contacts between individual subunits. Using electron microscopy and single-molecule reconstruction, we attempted to visualize the low-resolution conformations of a dimer of a de novo initiation-competent HCV RdRp.


Assuntos
Regulação Viral da Expressão Gênica , Hepacivirus/enzimologia , RNA Viral/genética , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/metabolismo , Dimerização , Hepacivirus/química , Hepacivirus/genética , Hepacivirus/fisiologia , Ligação Proteica , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/genética , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/química , Proteínas Virais/genética , Replicação Viral
10.
Phys Rev Lett ; 107(3): 037206, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21838401

RESUMO

We investigated the orbital and antiferromagnetic ordering behaviors of the half-doped bilayer manganite La(2-2x)Sr(1+2x)Mn2O7 (x ≃ 0.5) by using Mn L(2,3)-edge resonant soft x-ray scattering. Resonant soft x-ray scattering reveals the CE-type orbital order below T(oo) ≃ 220 K, which shows partial melting behavior below T(m) ≃ 165 K. We also found coexistence CE- and A-type antiferromagnetic orders. Both orders involve the CE-type orbital order with nearly the same orbital character and are coupled with each other. These results manifest that the ground state with the CE-type antiferromagnetic order is easily susceptible to destabilization into the A-type one even with a small fluctuation of the doping level, as suggested by the extremely narrow magnetic phase boundaries at x ≃ 0.5±0.005.

11.
Phys Rev Lett ; 105(25): 257204, 2010 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-21231622

RESUMO

We present an unreported magnetic configuration in epitaxial La(1-x) Sr(x) MnO3 (x ∼ 0.3) (LSMO) films grown on strontium titanate (STO). X-ray magnetic circular dichroism indicates that the remanent magnetic state of thick LSMO films is opposite to the direction of the applied magnetic field. Spectroscopic and scattering measurements reveal that the average Mn valence varies from mixed Mn(3+)/Mn(4+) to an enriched Mn3+ region near the STO interface, resulting in a compressive lattice along the a, b axis and a possible electronic reconstruction in the Mn e(g) orbital (d(3)z(2)-r(2). This reconstruction may provide a mechanism for coupling the Mn3+ moments antiferromagnetically along the surface normal direction, and in turn may lead to the observed reversed magnetic configuration.

12.
Phys Rev Lett ; 105(2): 027201, 2010 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-20867733

RESUMO

We report the formation of a novel ferromagnetic state in the antiferromagnet BiFeO3 at the interface with ferromagnet La(0.7)Sr(0.3)MnO3. Using x-ray magnetic circular dichroism at Mn and Fe L(2,3) edges, we discovered that the development of this ferromagnetic spin structure is strongly associated with the onset of a significant exchange bias. Our results demonstrate that the magnetic state is directly related to an electronic orbital reconstruction at the interface, which is supported by the linearly polarized x-ray absorption measurement at the oxygen K edge.

13.
Sci Adv ; 6(23): eaaz5132, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32548258

RESUMO

Iron is one of the most studied chemical elements due to its sociotechnological and planetary importance; hence, understanding its structural transition dynamics is of vital interest. By combining a short pulse optical laser and an ultrashort free electron laser pulse, we have observed the subnanosecond structural dynamics of iron from high-quality x-ray diffraction data measured at 50-ps intervals up to 2500 ps. We unequivocally identify a three-wave structure during the initial compression and a two-wave structure during the decaying shock, involving all of the known structural types of iron (α-, γ-, and ε-phase). In the final stage, negative lattice pressures are generated by the propagation of rarefaction waves, leading to the formation of expanded phases and the recovery of γ-phase. Our observations demonstrate the unique capability of measuring the atomistic evolution during the entire lattice compression and release processes at unprecedented time and strain rate.

14.
Science ; 248(4963): 1646-50, 1990 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-2194289

RESUMO

Transcription factor IID (TFIID) binds to the TATA box promoter element and regulates the expression of most eukaryotic genes transcribed by RNA polymerase II. Complementary DNA (cDNA) encoding a human TFIID protein has been cloned. The human TFIID polypeptide has 339 amino acids and a molecular size of 37,745 daltons. The carboxyl-terminal 181 amino acids of the human TFIID protein shares 80% identity with the TFIID protein from Saccharomyces cerevisiae. The amino terminus contains an unusual repeat of 38 consecutive glutamine residues and an X-Thr-Pro repeat. Expression of DNA in reticulocyte lysates or in Escherichia coli yielded a protein that was competent for both DNA binding and transcription activation.


Assuntos
Regiões Promotoras Genéticas , Saccharomyces cerevisiae/genética , Fatores de Transcrição/genética , Transcrição Gênica , Sequência de Aminoácidos , Clonagem Molecular , Escherichia coli/genética , Expressão Gênica , Células HeLa/metabolismo , Humanos , Dados de Sequência Molecular , Proteínas Recombinantes/metabolismo , Reticulócitos/metabolismo , Homologia de Sequência do Ácido Nucleico , Fator de Transcrição TFIID , Fatores de Transcrição/metabolismo
15.
Nat Commun ; 10(1): 3269, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332190

RESUMO

The discovery of charge- and spin-density-wave (CDW/SDW) orders in superconducting cuprates has altered our perspective on the nature of high-temperature superconductivity (SC). However, it has proven difficult to fully elucidate the relationship between the density wave orders and SC. Here, using resonant soft X-ray scattering, we study the archetypal cuprate La2-xSrxCuO4 (LSCO) over a broad doping range. We reveal the existence of two types of CDW orders in LSCO, namely CDW stripe order and CDW short-range order (SRO). While the CDW-SRO is suppressed by SC, it is partially transformed into the CDW stripe order with developing SDW stripe order near the superconducting Tc. These findings indicate that the stripe orders and SC are inhomogeneously distributed in the superconducting CuO2 planes of LSCO. This further suggests a new perspective on the putative pair-density-wave order that coexists with SC, SDW, and CDW orders.

16.
Phys Rev Lett ; 99(4): 043901, 2007 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-17678365

RESUMO

We have demonstrated nonlinear cross-phase modulation in electro-optic crystals using intense, single-cycle terahertz (THz) radiation. Individual THz pulses, generated by coherent transition radiation emitted by subpicosecond electron bunches, have peak energies of up to 100 microJ per pulse. The time-dependent electric field of the intense THz pulses induces cross-phase modulation in electro-optic crystals through the Pockels effect, leading to spectral shifting, broadening, and modulation of copropagating laser pulses. The observed THz-induced cross-phase modulation agrees well with a time-dependent phase-shift model.

17.
Mol Cell Biol ; 11(1): 63-74, 1991 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-1986253

RESUMO

Transcription factor IID from Saccharomyces cerevisiae (YIID) binds the TATA box element present in most RNA polymerase II promoters. In this work, partial proteolysis was used as a biochemical probe of YIID structure. YIID consists of a protease-sensitive amino terminus and a highly stable, protease-resistant carboxy-terminal core. The cleavage sites of the predominant chymotrypsin- and trypsin-derived fragments were mapped to amino acid residues 40 to 41 and 48 to 49, respectively, by amino-terminal peptide sequencing. Removal of the amino terminus resulted in a dramatic increase in the ability of YIID to form a stable complex with DNA during gel electrophoresis mobility shift assays and a two- to fourfold increase in DNA-binding affinity, as assayed by DNase I footprinting analysis. The carboxy-terminal 190-amino-acid core was competent for transcription in vitro and was similar in activity to native YIID. DNA containing a TATA element induced hypersensitive sites in the amino-terminal domain and stabilized the core domain to further proteolytic attack. Native YIID did not bind to a TATA box at 0 degrees C, whereas the carboxy-terminal DNA-binding domain did. These results suggest that YIID undergoes a conformational change upon binding to a TATA box. Southern blotting showed that the carboxy-terminal domain is highly conserved, while the amino-terminal domain diverged rapidly in evolution, even between closely related budding yeasts.


Assuntos
Proteínas de Ligação a DNA/ultraestrutura , Fatores de Transcrição/ultraestrutura , Sítios de Ligação , Proteínas Fúngicas/ultraestrutura , Expressão Gênica , Genes Fúngicos , Técnicas In Vitro , Estrutura Molecular , Mapeamento de Peptídeos , Regiões Promotoras Genéticas , Conformação Proteica , Proteínas Recombinantes , Sequências Reguladoras de Ácido Nucleico , Mapeamento por Restrição , Saccharomyces cerevisiae , Relação Estrutura-Atividade , Temperatura , Fator de Transcrição TFIID , Transcrição Gênica
18.
Nucleic Acids Res ; 29(17): 3576-82, 2001 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-11522827

RESUMO

How the 5'-terminus of the template affects RNA synthesis by viral RNA replicases is poorly understood. Using short DNA, RNA and RNA-DNA chimeric templates that can direct synthesis of replicase products, we found that DNA templates tend to direct the synthesis of RNA products that are shorter by 1 nt in comparison to RNA templates. Template-length RNA synthesis was also affected by the concentration of nucleoside triphosphates, the identity of the bases at specific positions close to the 5'-terminus and the C2'-hydroxyl of a ribose at the third nucleotide from the 5'-terminal nucleotide. Similar requirements are observed with two bromoviral replicases, but not with a recombinant RNA-dependent RNA polymerase. These results begin to define the interactions needed for the viral replicase to complete synthesis of viral RNA.


Assuntos
RNA Viral/biossíntese , RNA Polimerase Dependente de RNA/metabolismo , Sequência de Bases , Bromovirus/enzimologia , Bromovirus/genética , Domínio Catalítico , Cucumovirus/enzimologia , Cucumovirus/genética , DNA Viral/genética , RNA Polimerase Dependente de RNA/genética , Ribonucleotídeos/genética , Ribonucleotídeos/metabolismo , Ribose/metabolismo , Moldes Genéticos
19.
Transplant Proc ; 48(3): 900-4, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27234763

RESUMO

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor is an immunosuppressive drug used in kidney transplantation. Whether the mTOR inhibitor is associated with reduced risk of cancer development and mortality after kidney transplantation is controversial. METHODS: We conducted a nationwide population-based study. Patients who did not have malignancy history and received kidney transplantation between 2010 and 2013 were enrolled. Recipients who had mTOR inhibitors (n = 430) for more than 30 days comprised the study group; 1720 recipients who did not have mTOR inhibitors comprised the control group. The primary outcome is the development of cancer after kidney transplantation. These patients were followed until the first-time admission with diagnosis of cancer, death, or the end of 2014. A Cox proportional-hazard model was used to determine the risk of cancer development and all-cause mortality. RESULTS: During the 35-month median duration of observation, there were 16 and 61 patients with cancer development in the study group and the control group, respectively. The cancer incidence was 12.8 and 12.4 per 1000 person-years. There were 10 and 135 mortality cases, with the incidence rate of 7.8 and 26.9 per 1000 person-years. After multivariable adjustment, the mTOR inhibitors users were not associated with reduced risk of new cancer development as compared with control (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.46-1.60; P = .63), nor risk of all-cause mortality (HR, 0.70; 95% CI, 0.33-1.46; P = .34). CONCLUSIONS: The use of mTOR inhibitors was not associated with a reduction in the risk of cancer development and all-cause mortality in kidney transplantation recipients.


Assuntos
Inibidores Enzimáticos/efeitos adversos , Transplante de Rim/efeitos adversos , Neoplasias/epidemiologia , Vigilância da População , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Modelos de Riscos Proporcionais , Taiwan/epidemiologia , Adulto Jovem
20.
Oncogene ; 16(9): 1197-207, 1998 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-9528862

RESUMO

Mutant Epidermal Growth Factor Receptor (EGFR) oncoproteins lacking most of subdomains I and II of the extracellular region, a deletion which includes most of the first of two cysteine-rich sequences, have been observed in multiple human epithelial tumors, including malignant gliomas. These EGFR oncoproteins, designated deltaEGFR or EGFRvIII, confer increased tumorigenicity in vivo and are often coexpressed with full-length EGFR in human tumors. We have expressed an ectodomain-derived, carboxyl-terminal deletion mutant of the p185neu oncogene (T691stop) in human glioblastoma cells coexpressing endogenous EGFR and activated deltaEGFR oncoproteins. The p185neu ectodomain-derived mutant forms heterodimers with deltaEGFR proteins and reduces the phosphotyrosine content and kinase activity of deltaEGFR monomers. As a consequence of T691stop neu expression and surface localization, cell proliferation in conditions of full growth and reduced serum and anchorage-independent growth in soft agar was reduced in glioblastoma cells expressing either endogenous EGFR alone or coexpressing EGFR and elevated levels of deltaEGFRs. T691stop neu mutant receptors abrogate the dramatic growth advantage conferred by deltaEGFR in vivo, suggesting that physical associations primarily between subdomains III and IV of the p185neu and EGFR ectodomains are sufficient to modulate signaling from activated EGFR complexes. Receptor-based inhibitory strategies exploit the thermodynamic preference for erbB ectodomains to heterodimerize, thereby creating erbB receptor assemblies which are defective in signaling and do not internalize. Pharmaceuticals which mimic the p185neu ectodomain may therefore have important therapeutic applications in advanced human malignancies expressing erbB receptors.


Assuntos
Receptores ErbB/biossíntese , Glioblastoma/metabolismo , Receptor ErbB-2/biossíntese , Animais , Códon de Terminação , Receptores ErbB/metabolismo , Humanos , Mutagênese Sítio-Dirigida , Proteínas Oncogênicas/biossíntese , Ratos , Receptor ErbB-2/química , Receptor ErbB-2/metabolismo , Proteínas Recombinantes/biossíntese , Deleção de Sequência , Transdução de Sinais , Termodinâmica , Transfecção , Células Tumorais Cultivadas
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