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OBJECTIVE: Melatonin regulates the mammalian circadian rhythm and plays metabolic functions such as glucose homeostasis. Both melatonin receptors (MTNR1A and MTNR1B, encoded by the MTNR1A and MTNR1B genes, respectively) are expressed in pancreatic beta cells and mediate the glucometabolic roles of melatonin as well as insulin secretion. The MTNR1B gene is a well-known genetic risk factor in type 2 diabetes (T2D); however, little is known about the involvement of the MTNR1A gene in here T2D. We aimed to investigate whether MTNR1A is linked to and/or associated with familial T2D. SUBJECTS AND METHODS: We genotyped 14 single nucleotide polymorphisms within the MTNR1A gene in 212 peninsular Italian families with T2D. We performed parametric linkage and linkage disequilibrium analyses to investigate the role of MTNR1A variants in conferring T2D risk. We considered variants statistically significant if conferring linkage or linkage disequilibrium with p < 0.05. RESULTS: We found 3 novel variants (rs62350392, rs2119883, and rs13147179) significantly linked to and/or associated with T2D in multigenerational Italian families. CONCLUSIONS: This is the first study to report MTNR1A as a novel risk gene in T2D. Functional studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

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Introduction: Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it functions as an autocrine hormone. The synthesis of leptin in normal trophoblastic cells is regulated by different endogenous biochemical agents, but the regulation of placental leptin expression is still poorly understood. We have previously reported that 17β-estradiol up-regulates placental leptin expression through genomic and nongenomic mechanisms.Methods: To improve the understanding of estrogen receptor mechanisms in regulating leptin gene expression, we examined Sp1 transcription factor effect on estradiol leptin induction in human BeWo cell line.Results: We demonstrated that Sp1 induces leptin expression determined by qRT-PCR, Western blot and transient transfection experiments. We also found that estradiol induction effect on leptin expression is enhanced by the over expression of Sp1 factor. Moreover, estradiol effect was not evidenced when Sp1 binding site on leptin promoter is mutated, suggesting that estradiol action is dependent on Sp1. On the other hand we showed data that demonstrate that Sp1 induction of leptin expression is insensitive to the antiestrogen ICI 182 780. By over expression experiments, we have also found that Sp1 effect on leptin expression could be mediated by estrogen receptor alpha. Supporting this idea, the downregulation of estrogen receptor alpha level through a specific siRNA, abolished Sp1 effect on leptin expression.Discussion: Taken together all these evidences suggest a cooperative behavior between estrogen receptor alpha and Sp1 transcription factors to induce leptin transcription. [ABSTRACT FROM AUTHOR]

Abstract: Multidrug resistance (MDR) is a serious problem faced in the treatment of malignant tumors. In this study, we characterized the expression of non-homologous DNA end joining (NHEJ) components, a major DNA double strand break (DSB) repair mechanism in mammals, in K562 cell and its daunorubicin (DNR)-resistant subclone (K562/DNR). K562/DNR overexpressed major enzymes of NHEJ, DNA-PKcs and DNA ligase IV, and K562/DNR repaired DSB more rapidly than K562 after DNA damage by neocarzinostatin (MDR1-independent radiation-mimetic). Overexpressed DNA-PKcs and DNA ligase IV were also observed in DNR-resistant HL60 (HL60/DNR) cells as compared with parental HL60 cells. Expression level of DNA-PKcs mRNA paralleled its protein level, and the promoter activity of DNA-PKcs of K562/DNR was higher than that of K562, and the 5′-region between −49bp and the first exon was important for its activity. Because this region is GC-rich, we tried to suppress Sp1 family transcription factor using mithramycin A (MMA), a specific Sp1 family inhibitor, and siRNAs for Sp1 and Sp3. Both MMA and siRNAs suppressed DNA-PKcs expression. Higher serine-phosphorylated Sp1 but not total Sp1 of both K562/DNR and HL60/DNR was observed compared with their parental K562 and HL60 cells. DNA ligase IV expression of K562/DNR was also suppressed significantly with Sp1 family protein inhibition. EMSA and ChIP assay confirmed higher binding of Sp1 and Sp3 with DNA-PKcs 5′-promoter region of DNA-PKcs of K562/DNR than that of K562. Thus, the Sp1 family transcription factor affects important NHEJ component expressions in anti-cancer drug-resistant malignant cells, leading to the more aggressive MDR phenotype. [Copyright &y& Elsevier]

The development of diagnostic tools to assess restenosis risk after stent deployment may enable the intervention to be tailored to the individual patient, for example, by targeting the use of drug-eluting stent to high-risk patients, with the goal of improving safety and reducing costs. The CCNB1 gene (encoding cyclin B1) positively regulates cell proliferation, a key component of in-stent restenosis. Therefore, we hypothesized that single-nucleotide polymorphisms in CCNB1 may serve as useful tools in risk stratification for in-stent restenosis.We identified 3 single-nucleotide polymorphisms in CCNB1 associated with increased restenosis risk in a cohort of 284 patients undergoing coronary angioplasty and stent placement (rs350099: TT versus CC+TC; odds ratio [OR], 1.82; 95% confidence interval [CI], 1.09-3.03; P=0.023; rs350104: CC versus CT+TT; OR, 1.82; 95% CI, 1.02-3.26; P=0.040; and rs164390: GG versus GT+TT; OR, 2.27; 95% CI, 1.33-3.85; P=0.002). These findings were replicated in another cohort study of 715 patients (rs350099: TT versus CC+TC; OR, 1.88; 95% CI, 0.92-3.81; P=0.080; rs350104: CC versus CT+TT; OR, 2.23; 95% CI, 1.18-4.25; P=0.016; and rs164390: GG versus GT+TT; OR, 1.87; 95% CI, 1.03-3.47; P=0.040). Moreover, the haplotype containing all 3 risk alleles is associated with higher CCNB1 mRNA expression in circulating lymphocytes and increased in-stent restenosis risk (OR, 1.43; 95% CI, 1.00-1.823; P=0.039). The risk variants of rs350099, rs350104, and rs164390 are associated with increased reporter gene expression through binding of transcription factors nuclear factor-Y, activator protein 1, and specificity protein 1, respectively.Allele-dependent transcriptional regulation of CCNB1 associated with rs350099, rs350104, and rs164390 affects the risk of in-stent restenosis. These findings reveal these common genetic variations as attractive diagnostic tools in risk stratification for restenosis. [ABSTRACT FROM AUTHOR]

The interferon γ-inducible protein 16 (IFI16) is known as immune sensor of retroviral DNA intermediates. We show that IFI16 restricts HIV-1 independently of immune sensing by binding and inhibiting the host transcription factor Sp1 that drives viral gene expression. This antiretroviral activity and ability to bind Sp1 require the N-terminal pyrin domain and nuclear localization of IFI16, but not the HIN domains involved in DNA binding. Highly prevalent clade C HIV-1 strains are more resistant to IFI16 and less dependent on Sp1 than other HIV-1 subtypes. Furthermore, inhibition of Sp1 by IFI16 or pharmacologically by Mithramycin A suppresses reactivation of latent HIV-1 in CD4+ T cells. Finally, IFI16 also inhibits retrotransposition of LINE-1, known to engage Sp1, and murine IFI16 homologs restrict Friend retrovirus replication in mice. Thus, IFI16 restricts retroviruses and retrotransposons by interfering with Sp1-dependent gene expression, and evasion from this restriction may facilitate spread of HIV-1 subtype C. • IFI16 targets Sp1 to restrict HIV-1 transcription and LINE-1 retrotransposition • The N-terminal pyrin and NLS domains of IFI16 are sufficient for restriction • Sp1 inhibition by IFI16 or Mithramycin A suppresses reactivation of latent HIV-1 • Murine homologs of IFI16 restrict retroviral replication in vitro and in vivo The interferon γ-inducible protein 16 (IFI16) is an immune sensor of retroviral DNA intermediates. Hotter et al. demonstrate that IFI16 suppresses HIV-1 transcription and latency reactivation by interfering with Sp1-dependent gene expression. However, highly prevalent subtype C HIV-1 strains are less susceptible to IFI16 than other subtypes of HIV-1. [ABSTRACT FROM AUTHOR]