DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a ...multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610
Background
Extramammary Paget's disease (EMPD) is a rare skin cancer with relative high frequencies of germline and somatic mismatch repair (MMR) genes mutations. However, the methylation and ...expression of these genes have not been validated in EMPD.
Objective
This study aims to confirm the methylation and expression of MMR genes in EMPD.
Methods
Immunohistochemical (IHC) staining detection and Methylation‐specific PCR (MSP) were used to analyse MLH1, MSH2, MSH6 and PMS2 proteins’ expression and promoters’ methylation in 57 EMMD samples, and pyro‐sequence was used to find highly methylated CpG sites in MSH2 promoter.
Results
Immunohistochemical detection displayed reduced expression of MSH2 in 38.6% EMPD cases but normal expression of MLH1, MSH6 and PMS2 in all tumour tissues. Hypermethylation also was found in the promoter of MSH2 but not in other MMR genes. Pyrosequencing of MSH2 promoter showed CpG6 (‐87) and CpG3 (‐98) were the most common two methylated CpG dinucleotides. There is a significant correlation between reduced MSH2 expression and MSH2 methylation.
Conclusion
Reduced MSH2 expression and hypermethylation in this gene promoter were common genetic changes in EMPD, which expands our understanding of the role of MMR function in this skin cancer.
Summary
The mechanisms by which the maize antioxidant Cat1 gene responds to abscisic acid (ABA) and osmotic stress have been investigated. Results show that during late embryogenesis, Cat1 expression ...in vivo is independent of endogenous ABA levels. However, exogenously applied ABA significantly enhances Cat1 expression. Transient assays using particle bombardment show that the proximal ABRE2 element on the Cat1 promoter is responsible for the induction of Cat1 expression by ABA. We further show that ABA induces the expression of Cat1 via the interaction between ABRE2 and one of its binding proteins, CBF1 (Cat1 binding factor 1). Using ABA‐deficient mutant embryos, we show that osmotic stress induces Cat1 expression through two alternate signal transduction pathways: an ABA signaling pathway leading to the interaction between the ABRE2 motif and CBF1, and a pathway via the interaction of ABRE2 and CBF2 (Cat1 binding factor 2) that is independent of ABA. The data presented clearly suggest that hydrogen peroxide (H2O2) plays an important intermediary role in the ABA signal transduction pathway leading to the induction of the Cat1 gene.
•Molten KOH etching epitaxial layers grown at various conditions was conducted.•Etching pits of epitaxial defects such as TSD, TED and BPD were observed.•Density of etching pits decreases with the ...thickness of the epitaxial layer increasing.•Appropriate C/Si ratio will improve the quality of epitaxial layer.
Epitaxial defects such as threading screw dislocation (TSD), basal plane dislocation (BPD) and so on will seriously reduce the reverse voltage or increase leakage current of power devices. We studied the classification and statistics of the above several types of 4H-SiC epitaxial defects, by using molten KOH etching the epitaxial layer to explore and trace the origin of epitaxial defects. Studies have shown that the formation principles of various epitaxial defects are related to dislocations, and the growth parameters such as carbon-to-silicon ratio and growth time have paid a significant role on epitaxial defects.
Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in ...African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD rs41302867 P = 0.033 (OR = 0.50), and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69). Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD P = 0.036 (OR = 0.54) and hypertension attributed ESKD H-ESKD, P = 0.029 (OR = 0.50). A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants.
The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance ...develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.
Seventy-one adults with advanced STS who received ⩽ 2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).
There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N = 11) over single agent (N = 10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P = 0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).
While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
The aim of this study was to clarify the role of LINC00511 in regulating the proliferative ability of cardiomyocytes undergoing ischemia/reperfusion (I/R) injury by absorbing miRNA-515-5p.
Adult male ...C57BL/6 mice were subjected to I/R injury, and I/R model was constructed in vivo. Primary cardiomyocytes were isolated from 1-2 days-old male mice and treated with H2O2 to establish the I/R model in vitro. The relative expression level of LINC00511 was determined after ligation of the anterior descending coronary artery (LAD) in mice or H2O2 induction in primary cardiomyocytes for different time points, respectively. The regulatory effect of LINC00511 on the viability of H2O2-treated cardiomyocytes was assessed. Subsequently, the interaction between LINC00511 and miRNA-515-5p was evaluated by Dual-Luciferase Reporter Gene Assay. Furthermore, the viability and 5-Ethynyl-2'-deoxyuridine (EdU)-positive rate influenced by LINC00511/miRNA-515-5p were examined.
LINC00511 was gradually downregulated with the prolongation of I/R procedures in mice or H2O2 treatment in primary cardiomyocytes. The overexpression of LINC00511 significantly elevated the viability and EdU-positive rate in H2O2-treated cardiomyocytes. LINC00511 could bind to miRNA-515-5p. Meanwhile, there was a negative correlation between the levels of LINC00511 and miRNA-515-5p. In addition, the overexpression of miRNA-515-5p reversed the promoting effect of LINC00511 on the proliferative ability of H2O2-treated cardiomyocytes.
LINC00511 accelerates the proliferation of cardiomyocytes after I/R by targeting miRNA-515-5p.
The phase stability, elastic properties, electronic structure and thermodynamics properties of ZrPt compounds are investigated by first-principles approach. The calculated formation enthalpies show ...that the CrB-type phase at ground state is more stable than that of CsCl-type, which is in good agreement with the experimental phenomena. The bulk modulus of CrB-type is close to the CsCl-type phase. However, the shear constant C44 and shear modulus for the former are two times larger than the latter. Furthermore, we found that the Debye temperature of CrB-type (288.5K) is higher than that of CsCl-type (186K) phase, indicates that the atomic cohesion of the former is stronger than the latter at ground state.
Two related Rho GTPase-activating proteins, DLC-1 (deleted in liver cancer 1) and DLC-2, are emerging as bona fide tumor suppressor genes that inhibit cancer cell growth. In this report, we ...characterized a gene on chromosome Xq13 that encodes DLC-3 (also known as KIAA0189 and STARD8), a third member of the DLC family. The DLC-3 gene has transcripts with alternative 5' ends, one of which, DLC-3alpha, encodes an 1103-amino acid polypeptide highly similar to DLC-1 and DLC-2. A second isoform (DLC-3beta) would yield a protein lacking the N-terminal sterile alpha motif domain. The DLC-3 gene is widely expressed in normal tissues, but DLC-3 mRNA levels were low or absent in a significant number of breast, ovarian, liver and prostate cancer cell lines. Using a cancer profiling array to compare matched tumor and normal human tissues, downregulation of DLC-3 mRNA was observed in kidney, lung, ovarian, uterine and breast cancer samples. By quantitative reverse transcriptase-polymerase chain reaction, DLC-3 expression was reduced in primary prostate carcinomas relative to normal prostate tissue. Transfection of human breast and prostate cancer cells with a DLC-3alpha expression vector inhibited cell proliferation, colony formation and growth in soft agar. These results indicate that deregulation of DLC-3 may contribute to breast and prostate tumorigenesis.
The occupation mechanism and influence of B doping on the electronic and mechanical properties of RuAl
2
semiconducting compound have been investigated using first-principles calculations. Four ...possible B doping sites are considered. The results show that B-doped RuAl
2
is thermodynamically stable. In particular, B element prefers to occupy B(4) site in comparison with other sites. Importantly, B doping improves the electronic properties of RuAl
2
by shifting the Al 3
p
and Ru 4
d
states from the Fermi level (
E
F
) to the valence band. Although B doping weakens the resistance to volume and shear deformation as well as the elastic stiffness of RuAl
2
, it improves the ductility due to the formation of Ru-B and Al-B bonds. Therefore, it can be concluded that B is a favorable doping element to improve the electronic properties and ductility of RuAl
2
semiconducting compound.
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