RESUMO
An increasing number of studies have indicated that long noncoding RNAs (lncRNAs) are involved in the regulation of non-small-cell lung cancer (NSCLC). Nevertheless, there are still numerous undiscovered mechanisms underlying this molecular regulation. Here, the results illustrated that CASC11 is overexpressed in NSCLC tumor tissues and cell lines, which is closely related to the clinical features of NSCLC and poor survival. In functional experiments, CASC11 was shown to promote proliferation and cycle progression and enhance NSCLC tumorigenesis. In mechanical investigations, CASC11 was shown to target the miR-498/FOXO3 axis via a canonical competing endogenous RNA (ceRNA). In return, the transcription factor FOXO3 targets the CASC11 promoter region, thereby accelerating its transcription. Our findings demonstrate a crucial role for CASC11 as an oncogene in promoting NSCLC. These results reveal that CASC11 might be a potential therapeutic target for NSCLC.
Assuntos
Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Proteína Forkhead Box O3/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Células Cultivadas , HumanosRESUMO
OBJECTIVE: To explore the relationship between cancer awareness and the survival of the patients with non-small cell lung carcinoma (NSCLC).â© Methods: A total of 865 NSCLC patients were screened for the risk factors, including age, gender, address, tumor/lymph nodes/metastasis (TNM) stage, and cancer awareness. Survival of the patients was calculated by Kaplan-Meier method and Cox regression analysis.â© Results: After an average observation time of 304 d (ranging from 0 to 4 718 d), 62 of the 394 patients in the cancer awareness group survived, whereas 26 of the 471 patients in the cancer concealment group survived. Cancer-specific and all-cause survival was poorer in the cancer concealment group (P<0.001 for each, log-rank test). Cox multivariate regression analysis showed that cancer concealment displayed significantly lower cancer-specific survival [hazard ratio (HR)=1.534, 95% confidence interval (CI) 1.320 to 1.784, P<0.001] and all-cause survival (HR=1.558, 95% CI 1.346 to 1.803, P<0.001).â© Conclusion: Cancer concealment is associated with a poor survival of NSCLC patients, which may prohibit the patients from obtaining the real "right to survival".
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Metástase Linfática , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
The proteins securin and cyclin B are destroyed in mitosis by the ubiquitin/proteasome system. This destruction is important to mitotic progression. The N-terminal regions of these proteins contain the sequence features recognized by the ubiquitination system. We have demonstrated using circular dichroism and 1-D and 2-D nuclear magnetic resonance that these rather substantial regions are natively unfolded. Based on these findings, we propose a model that helps to explain previously enigmatic observations.
Assuntos
Proteínas de Ciclo Celular , Ciclina B/química , Ciclina B/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae , Sequência de Aminoácidos , Dicroísmo Circular , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Dados de Sequência Molecular , Dobramento de Proteína , Securina , Homologia de Sequência de Aminoácidos , Ubiquitina/metabolismoRESUMO
Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease that caused pandemic spread in 2003. The etiological agent of SARS is a novel coronavirus (SARS-CoV). The coronaviral surface spike protein S is a type I transmembrane glycoprotein that mediates initial host binding via the cell surface receptor angiotensin-converting enzyme 2 (ACE2), as well as the subsequent membrane fusion events required for cell entry. Here we report the crystal structure of the S1 receptor binding domain (RBD) in complex with a neutralizing antibody, 80R, at 2.3 A resolution, as well as the structure of the uncomplexed S1 RBD at 2.2 A resolution. We show that the 80R-binding epitope on the S1 RBD overlaps very closely with the ACE2-binding site, providing a rationale for the strong binding and broad neutralizing ability of the antibody. We provide a structural basis for the differential effects of certain mutations in the spike protein on 80R versus ACE2 binding, including escape mutants, which should facilitate the design of immunotherapeutics to treat a future SARS outbreak. We further show that the RBD of S1 forms dimers via an extensive interface that is disrupted in receptor- and antibody-bound crystal structures, and we propose a role for the dimer in virus stability and infectivity.
Assuntos
Anticorpos Antivirais/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo , Anticorpos Antivirais/imunologia , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Humanos , Glicoproteínas de Membrana/imunologia , Modelos Moleculares , Testes de Neutralização , Ligação Proteica , Estrutura Terciária de Proteína , Síndrome Respiratória Aguda Grave , Glicoproteína da Espícula de Coronavírus , Proteínas do Envelope Viral/imunologiaRESUMO
Cell cycle progression is controlled at several different junctures by the targeted destruction of cell cycle regulatory proteins. These carefully orchestrated events include the destruction of the securin protein to permit entry into anaphase, and the destruction of cyclin B to permit exit from mitosis. These destruction events are mediated by the ubiquitin/proteasome system. The human ubiquitin-conjugating enzyme, UbcH10, is an essential mediator of the mitotic destruction events. We report here the 1.95-A crystal structure of a mutant UbcH10, in which the active site cysteine has been replaced with a serine. Functional analysis indicates that the mutant is active in accepting ubiquitin, although not as efficiently as wild-type. Examination of the crystal structure reveals that the NH2-terminal extension in UbcH10 is disordered and that a conserved 3(10)-helix places a lysine residue near the active site. Analysis of relevant mutants demonstrates that for ubiquitin-adduct formation the presence or absence of the NH2-terminal extension has little effect, whereas the lysine residue near the active site has significant effect. The structure provides additional insight into UbcH10 function including possible sites of interaction with the anaphase promoting complex/cyclosome and the disposition of a putative destruction box motif in the structure.