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Obese patients have chronic, low-grade inflammation that predisposes to type 2 diabetes and results, in part, from dysregulated visceral white adipose tissue (WAT) functions. The specific signaling ...pathways underlying WAT dysregulation, however, remain unclear. Here we report that the PPARγ signaling pathway operates differently in the visceral WAT of lean and obese mice. PPARγ in visceral, but not subcutaneous, WAT from obese mice displayed increased sensitivity to activation by its agonist rosiglitazone. This increased sensitivity correlated with increased expression of the gene encoding the ubiquitin hydrolase/ligase ubiquitin carboxyterminal esterase L1 (UCH-L1) and with increased degradation of the PPARγ heterodimerization partner retinoid X receptor a (RXRα), but not RXRβ, in visceral WAT from obese humans and mice. Interestingly, increased UCH-L1 expression and RXRα proteasomal degradation was induced in vitro by conditions mimicking hypoxia, a condition that occurs in obese visceral WAT. Finally, PPARγ-RXRβ heterodimers, but not PPARγ-RXRα complexes, were able to efficiently dismiss the transcriptional corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) upon agonist binding. Increasing the RXRα/RXRβ ratio resulted in increased PPARγ responsiveness following agonist stimulation. Thus, the selective proteasomal degradation of RXRα initiated by UCH-L1 upregulation modulates the relative affinity of PPARγ heterodimers for SMRT and their responsiveness to PPARγ agonists, ultimately activating the PPARγ-controlled gene network in visceral WAT of obese animals and humans.
G-quadruplex (G4) structures in intron 3 of the p53 pre-mRNA modulate intron 2 splicing, altering the balance between the fully spliced p53 transcript (FSp53, encoding full-length p53) and an ...incompletely spliced transcript retaining intron 2 (p53I2 encoding the N-terminally truncated Δ40p53 isoform). The nucleotides forming G4s overlap the polymorphism rs17878362 (A1 wild-type allele, A2 16-base pair insertion) which is in linkage disequilibrium with rs1642785 in intron 2 (c.74+38 G>C). Biophysical and biochemical analyses show rs17878362 A2 alleles form similar G4 structures as A1 alleles although their position is shifted with respect to the intron 2 splice acceptor site. In addition basal FSp53 and p53I2 levels showed allele specific differences in both p53-null cells transfected with reporter constructs or lymphoblastoid cell lines. The highest FSp53 and p53I2 levels were associated with combined rs1642785-GG/rs17878362-A1A1 alleles, whereas the presence of rs1642785-C with either rs17878362 allele was associated with lower p53 pre-mRNA, total TP53, FSp53 and p53I2 levels, due to the lower stability of transcripts containing rs1642785-C. Treatment of lymphoblastoid cell with the G4 binding ligands 360A or PhenDC3 or with ionizing radiation increased FSp53 levels only in cells with rs17878362 A1 alleles, suggesting that under this G4 configuration full splicing is favoured. These results demonstrate the complex effects of intronic TP53 polymorphisms on G4 formation and identify a new role for rs1642785 on mRNA splicing and stability, and thus on the differential expression of isoform-specific transcripts of the TP53 gene.
Guanine-rich sequences found in telomeres and oncogene promoters have the ability to form G-quadruplex structures. In this paper we describe the use of a virtual screening assay to search a database ...of FDA-approved compounds for compounds with the potential to bind G-quadruplex DNA. More than 750 telomerase inhibitors were identified in a literature search as acting through G-quadruplex stabilization, and from evaluation of these compounds, theoretical models capable of discriminating new compounds that bind G-quadruplex DNA were developed. Six compounds predicted to bind to the G-quadruplex structure were tested for their ability to bind to the human telomeric DNA sequence. Prochloroperazine, promazine, and chlorpromazine stabilized the G-quadruplex structure as determined by fluorescence resonance energy transfer techniques. These compounds also bound to promoter sequences of oncogenes such as c-myc and K-ras. Amitriptyline, imipramine, and loxapine were less stabilizing but did bind to the G-quadruplex. The ability of prochloroperazine, promazine, and chlorpromazine to recognize G-quadruplex structures was confirmed using a fluorescent intercalator displacement assay, in which displacement of thiazole orange from G-quadruplex structures was demonstrated. Interestingly, these compounds exhibited selectivity for the G-quadruplex structure as all had poor affinity for the duplex sequence.
We report the synthesis of two new series of triangular aromatic platforms, either with three aminoalkyl side chains (triazatrinaphthylene series, TrisK: six compounds), or without side chains ...(triazoniatrinaphthylene, TrisQ). The quadruplex–DNA binding behavior of the two series, which differ essentially by the localization of the cationic charges, was evaluated by means of FRET‐melting and G4‐FID assays. For the trisubstituted triazatrinaphthylenes (TrisK), the length of the substituents and the presence of terminal hydrogen‐bond‐donor groups (NH2) were shown to be crucial for ensuring a high quadruplex affinity (ΔT1/2 values of up to 20 °C at 1 μM for the best candidate, TrisK3‐NH) and selectivity versus duplex DNA. Subsequently, comparison of data collected on both the telomeric‐ and c‐myc‐quadruplex showed that the nonsubstituted TrisQ is even more efficient than TrisK3‐NH, both in terms of quadruplex affinity (ΔT1/2=26 °C in K+ buffer) and selectivity versus duplex DNA. Structural considerations conducted with the c‐myc quadruplex indicate that both TrisK3‐NH and TrisQ stack well onto the G‐quartet but in an offset position, which might be influenced by the formation of multiple hydrogen bonds with the target in the former case. Finally, the nonsubstituted TrisQ displays a binding profile very similar to some of the best quadruplex binders, BRACO‐19 and bisquinolinium 360A, used herein as references, and thereby represents a highly promising novel molecular design for quadruplex recognition.
A new star! Two new series of C3‐symmetric, star‐shaped aromatic compounds, differing in the presence or the absence of side chains, were synthesized. Comparison of data collected with telomeric and c‐myc quadruplexes shows that the nonsubstituted trisquinolizinium derivative (TrisQ) is more efficient than the trisubstituted triazatrinaphthalene derivatives (TrisK) for quadruplex recognition. TrisQ is thus a highly promising quadruplex binder that rivals the performance of the well‐established ligand BRACO‐19.
Recent studies indicate that i‐DNA, a four‐stranded cytosine‐rich DNA also known as the i‐motif, is actually formed in vivo; however, a systematic study on sequence effects on stability has been ...missing. Herein, an unprecedented number of different sequences (271) bearing four runs of 3–6 cytosines with different spacer lengths has been tested. While i‐DNA stability is nearly independent on total spacer length, the central spacer plays a special role on stability. Stability also depends on the length of the C‐tracts at both acidic and neutral pHs. This study provides a global picture on i‐DNA stability thanks to the large size of the introduced data set; it reveals unexpected features and allows to conclude that determinants of i‐DNA stability do not mirror those of G‐quadruplexes. Our results illustrate the structural roles of loops and C‐tracts on i‐DNA stability, confirm its formation in cells, and allow establishing rules to predict its stability.
i‐DNA is an emerging non‐canonical DNA secondary structure as an anticancer target and as a basic element in the programmable bionanotechnology. A large number of i‐DNA‐prone sequences were tested to disclose how primary sequences determine the i‐DNA stability both in vitro and in cells.
Wählerisch: Eine Familie nichtmakrocyclischer G‐Quadruplexbinder mit alternierenden Oxazol‐ und Pyridinmotiven wurde hergestellt. Das gezeigte heptacyclische Derivat hat eine neuartige ...Bindungspräferenz für bestimmte Quadruplextopologien: Es erkennt exklusiv den humanen telomeren Quadruplex in Na+‐, nicht aber in K+‐Puffer. Dieses einzigartige Quadruplexbindungsprofil hängt stark von der Ligandengröße ab und könnte von Furchenwechselwirkungen herrühren.
The syntheses of novel 2,4-bis(substituted-aminomethyl)phenylphenylquinazolines 12 and 2,4-bis(substituted-aminomethyl)phenylphenylquinolines 13 are reported here in six steps starting from various ...halogeno-quinazoline-2,4-(1H,3H)-diones or substituted anilines. The antiproliferative activities of the products were determined in vitro against a panel of breast (MCF-7 and MDA-MB-231), human adherent cervical (HeLa and SiHa), and ovarian (A2780) cell lines. Disubstituted 6- and 7-phenyl-bis(3-dimethylaminopropyl)aminomethylphenyl-quinazolines 12b, 12f, and 12i displayed the most interesting antiproliferative activities against six human cancer cell lines. In the series of quinoline derivatives, 6-phenyl-bis(3-dimethylaminopropyl)aminomethylphenylquinoline 13a proved to be the most active. G-quadruplexes (G4) stacked non-canonical nucleic acid structures found in specific G-rich DNA, or RNA sequences in the human genome are considered as potential targets for the development of anticancer agents. Then, as small aza-organic heterocyclic derivatives are well known to target and stabilize G4 structures, their ability to bind G4 structures have been determined through FRET melting, circular dichroism, and native mass spectrometry assays. Finally, telomerase inhibition ability has been also assessed using the MCF-7 cell line.
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