Induction of apoptosis by the retinoid inducible growth regulator RIG1 depends on the NC motif in HtTA cervical cancer cells

<p>Abstract</p> <p>Background</p> <p>Retinoid-inducible gene 1 (RIG1), also known as tazarotene-induced gene 3 or retinoic-acid receptor responder 3, is a growth regulator, which induces apoptosis and differentiation. RIG1 is classified into the NC protein family. This study investigated functional domains and critical amino acids associated with RIG1-mediated cell death and apoptosis.</p> <p>Results</p> <p>Using enhanced green fluorescence protein (EGFP)-tagged RIG1 variants, RIG1 proteins with deletion at the NC domain significantly decreased cell death induced by RIG1, and fusion variants containing only the NC domain significantly induced apoptosis of HtTA cervical cancer cells. The EGFP-RIG1-induced apoptosis was significantly decreased in cells expressing N¹¹²C¹¹³motif double- (NC→FG) or triple- (NCR→FGE) mutated RIG1 variants. Using dodecapeptides, nuclear localization and profound cell death was observed in HtTA cells expressing wild type RIG1_111–123or Leu¹²¹-mutated RIG1_111–123:L→ C peptide, but peptides double- or triple-mutated at the NC motif alone, RIG1_111–123:NC→FG or RIG1_111–123:NCR→FGE, were cytoplasmically localized and did not induce apoptosis. The RIG1_111–123also induced apoptosis of A2058 melanoma cells but not normal human fibroblasts.</p> <p>Conclusion</p> <p>The NC domain, especially the NC motif, plays the major role in RIG1-mediated pro-apoptotic activity. The RIG1_111–123dodecapeptide exhibited strong pro-apoptotic activity and has potential as an anticancer drug.</p

Multicolor Photometry Study of the Galaxy Cluster A2589: Dynamics, Luminosity Function and Star Formation History

In this paper we present a multicolor photometry for A2589 ($z=0.0414$) with 15 intermediate bands in the Beijing-Arizona-Taiwan-Connecticut (BATC) system which covers an optical wavelength range from 3000 \AA\ to 10000 \AA. The spectral energy distributions (SEDs) for more than 5000 sources are achieved down to {\it V} $\sim$ 20 mag in about 1 deg$^{2}$ field. A2589 has been also covered by the Sloan Digital Sky Survey (SDSS) in photometric mode only. A cross-identification of the BATC-detected galaxies with the SDSS photometric catalog achieves 1199 galaxies brighter than $i=19.5$ mag, among which 68 member galaxies with known spectroscopic redshifts are found. After combining the SDSS five-band photometric data and the BATC SEDs, the technique of photometric redshift is applied to these galaxies for selecting faint member galaxies. The color-magnitude relation is taken as a further restriction of early-type cluster galaxies. As a result, 106 galaxies are newly selected as member galaxies. Spatial distribution of member galaxies shows a north-south elongation which agrees with the X-ray brightness profile and the orientation of central cD galaxy, NGC 7647. No substructures are detected on the basis of positions and radial velocities of cluster galaxies, indicating that A2589 is a well-relaxed system. The luminosity function of A2589 exhibits a peak at $M_{R} \sim -20$ mag and a dip at $M_{R} \sim -19$ mag. The low-density outer regions are the preferred habitat of faint galaxies. With the evolutionary population synthesis model, PEGASE, the environmental effect on the star formation properties for 68 spectroscopically confirmed member galaxies is studied. The outlier faint galaxies tend to have longer time scales of star formation, shorter mean stellar ages, and lower metallicities of interstellar medium, which can be interpreted in the context of hierarchical cosmological scenario.Comment: 2011 Accepted to A

Altered Activity of SK Channel Underpins Morphine Withdrawal Relevant Psychiatric Deficiency in Infralimbic to Accumbens Shell Pathway

Drug addiction can be viewed as a chronic psychiatric disorder that is related to dysfunction of neural circuits, including reward deficits, stress surfeits, craving changes, and compromised executive function. The nucleus accumbens (NAc) plays a crucial role in regulating craving and relapse, while the medial prefrontal cortex (mPFC) represents a higher cortex projecting into the NAc that is active in the management of executive function. In this study, we investigated the role of the small conductance calcium-activated potassium channels (SK channels) in NAc and mPFC after morphine withdrawal. Action potential (AP) firing of neurons in the NAc shell was enhanced via the downregulations of the SK channels after morphine withdrawal. Furthermore, the expression of SK2 and SK3 subunits in the NAc was significantly reduced after 3 weeks of morphine withdrawal, but was not altered in the dorsal striatum. In mPFC, the SK channel subunits were differentially expressed. To be specific, the expression of SK3 was upregulated, while the expression of SK2 was unchanged. Furthermore, the AP firing in layer 5 pyramidal neurons of the infralimbic (IL) cortex was decreased via the upregulations of the SK channel-related tail current after 3 weeks of morphine withdrawal. These results suggest that the SK channel plays a specific role in reward circuits following morphine exposure and a period of drug withdrawal, making it a potential target for the prevention of relapse

Single Nucleotide Polymorphisms of 8 Inflammation-related Genes and their Associations with Smoking-related Cancers

Tobacco smoke and its metabolites are carcinogens that increase tissue oxidative stress and induce target tissue inflammation. We hypothesized that genetic variation of inflammatory pathway genes plays a role in tobacco-related carcinogenesis and is modified by tobacco smoking. We evaluated the association of 12 single nucleotide polymorphisms of 8 inflammation-related genes with tobacco-related cancers (lung, oropharynx, larynx, esophagus, stomach, liver, bladder, and kidney) using 3 case-control studies from: Los Angeles (population-based; 611 lung and 553 upper aero-digestive tract cancer cases and 1,040 controls), Taixing, China (population-based; 218 esophagus, 206 stomach, 204 liver cancer cases, and 415 controls), and Memorial Sloan-Kettering Cancer Center (hospital-based; 227 bladder cancer cases and 211 controls). After adjusting for age, education, ethnicity, gender, and tobacco smoking, IL10 rs1800871 was inversely associated with oropharyngeal cancer (CT+TT vs. CC adjusted odds ratio [aOR]: 0.69, 95% confidence interval [CI]: 0.50-0.95), and was positively associated with lung cancer among never smokers (TT vs. CT+CC aOR: 2.5, 95% CI: 1.3-5.1) and inversely with oropharyngeal cancer among ever smokers (CT+TT vs. CC aOR: 0.63, 95% CI: 0.41-0.95). Among all pooled never smokers (588 cases and 816 controls), TNF rs1799964 was inversely associated with smoking-related cancer (CC vs. CT+TT aOR: 0.36, 95% CI: 0.17-0.77). Bayesian correction for multiple comparisons suggests that chance is unlikely to explain our findings (although epigenetic mechanisms may be in effect), which support our hypotheses, suggesting that IL10 rs1800871 is a susceptibility marker for oropharyngeal and lung cancers, and that TNF rs1799964 is associated with smoking-related cancers among never smokers. © 2010 UICC

G protein-coupled receptor kinase 5 mediates Tazarotene-induced gene 1-induced growth suppression of human colon cancer cells

<p>Abstract</p> <p>Background</p> <p>Tazarotene-induced gene 1 (TIG1) is a retinoid-inducible type II tumour suppressor gene. The B isoform of TIG1 (TIG1B) inhibits growth and invasion of cancer cells. Expression of TIG1B is frequently downregulated in various cancer tissues; however, the expression and activities of the TIG1A isoform are yet to be reported. Therefore, this study investigated the effects of the TIG1A and TIG1B isoforms on cell growth and gene expression profiles using colon cancer cells.</p> <p>Methods</p> <p>TIG1A and TIG1B stable clones derived from HCT116 and SW620 colon cancer cells were established using the GeneSwitch system; TIG1 isoform expression was induced by mifepristone treatment. Cell growth was assessed using the WST-1 cell proliferation and colony formation assays. RNA interference was used to examine the TIG1 mediating changes in cell growth. Gene expression profiles were determined using microarray and validated using real-time polymerase chain reaction, and Western blot analyses.</p> <p>Results</p> <p>Both TIG1 isoforms were expressed at high levels in normal prostate and colon tissues and were downregulated in colon cancer cell lines. Both TIG1 isoforms significantly inhibited the growth of transiently transfected HCT116 cells and stably expressing TIG1A and TIG1B HCT116 and SW620 cells. Expression of 129 and 55 genes was altered upon induction of TIG1A and TIG1B expression, respectively, in stably expressing HCT116 cells. Of the genes analysed, 23 and 6 genes were upregulated and downregulated, respectively, in both TIG1A and TIG1B expressing cells. Upregulation of the G-protein-coupled receptor kinase 5 (GRK5) was confirmed using real-time polymerase chain reaction and Western blot analyses in both TIG1 stable cell lines. Silencing of TIG1A or GRK5 expression significantly decreased TIG1A-mediated cell growth suppression.</p> <p>Conclusions</p> <p>Expression of both TIG1 isoforms was observed in normal prostate and colon tissues and was downregulated in colon cancer cell lines. Both TIG1 isoforms suppressed cell growth and stimulated GRK5 expression in HCT116 and SW620 cells. Knockdown of GRK5 expression alleviated TIG1A-induced growth suppression of HCT116 cells, suggesting that GRK5 mediates cell growth suppression by TIG1A. Thus, TIG1 may participate in the downregulation of G-protein coupled signaling by upregulating GRK5 expression.</p

SEC16A variants predispose to chronic pancreatitis by impairing ER‐to‐Golgi Transport and inducing ER stress

Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next‐generation sequencing of the SEC16A gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous SEC16A variants in patients (4.90% vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26–2.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67–4.50) and in a biobank meta‐analysis (OR, 1.16; 95% CI, 1.04–1.31). Notably, Chinese CP patients with SEC16A variants exhibit a median onset age 5 years earlier than those without (40.0 vs 45.0; p = 0.012). Functional studies using three CRISPR/Cas9‐edited HEK293T cell lines show that loss‐of‐function SEC16A variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. Sec16a+/− mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a+/+, are further generated. In cerulein‐stimulated pancreatitis models, Sec16a+/− mice display heightened pancreatic inflammation and fibrosis compared to wild‐type mice. These findings implicate a novel pathogenic mechanism predisposing to CP

Corrigendum to: The TianQin project: current progress on science and technology

In the originally published version, this manuscript included an error related to indicating the corresponding author within the author list. This has now been corrected online to reflect the fact that author Jun Luo is the corresponding author of the article