No abstract

This report describes the association between birth weight (BW) and obesity. Screening of 478 citations from five electronic databases resulted in the inclusion of 33 studies, most of medium quality. The meta-analysis included 20 of these published studies. The 13 remaining articles did not provide sufficient dichotomous data and were systematically reviewed, revealing results consistent with the meta-analysis. Our results revealed that high BW (>4000 g) was associated with increased risk of obesity (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.91-2.24) compared with subjects with BW ≤ 4000 g. Low BW (<2500 g) was associated with decreased risk of obesity (OR, 0.61; 95% CI, 0.46-0.80) compared with subjects with BW ≥ 2500 g. However, when two studies exhibited selection bias were removed, the results indicated no significant association between low BW and obesity (OR, 0.77; 95% CI, 0.58-1.04). Sensitivity analyses showed that differences in the study design, sample size and quality grade of the study had an effect on the low BW/obesity association, which low BW was not associated with the risk of obesity in cohort studies, studies with large sample sizes and studies with high quality grades. Pooled results were similar when normal birth weight (2500-4000 g) was used as the reference category. Subgroup analyses based on different growth and developmental stages (pre-school children, school children and adolescents) also revealed that high BW was associated with increased risk of obesity from childhood to early adulthood. No significant evidence of publication bias was present. These results suggest that high BW is associated with increased risk of obesity and may serve as a mediator between prenatal influences and later disease risk.

No abstract

The Signal Transducer and Activator of Transcription (STAT) family of proteins was first discovered in the 1990's as key proteins in cytokine signaling. Since then, the field has greatly advanced in the past 15 years, providing significant insight into the structure, function, and regulation of STATs. STATs are latent cytoplasmic transcription factors consisting of seven mammalian members. They are Tyr phosphorylated upon activation, a post-translational modification critical for dimerization, nuclear import, DNA binding, and transcriptional activation. In recent years, unphosphorylated STATs have also been observed to dimerize and drive transcription, albeit by yet an obscure mechanism. In addition, the function of cytoplasmic STATs is beginning to emerge. Here, we describe the structure, function, and regulation of both unphosphorylated and phosphorylated STATs. STAT isoforms from alternative splicing or proteolytic processing, and post-translational modifications affecting STAT activities are also discussed.

Stat3 is a member of the signal transducer and activator of transcription family, which is important in cytokine signaling. Gene ablation studies have revealed a requirement for Stat3 in diverse biological processes (Akira, S. 2000. Oncogene. 19: 2607–2611; Levy, D.E., and C.K. Lee. 2002. J. Clin. Invest. 109:1143–1148). Previously, the function of Stat3 had been attributed exclusively to its transcriptional activity in the nucleus. In this study, we reveal an interaction between Stat3 and the microtubule (MT)-destabilizing protein stathmin. Stathmin did not overtly affect ligand-stimulated Stat3 activation. In contrast, the expression of Stat3 is required for the stabilization of MTs and cell migration. We further demonstrate that Stat3-containing cells are resistant to the MT-destabilizing effect of stathmin overexpression. In addition, down-regulation of stathmin protein levels in Stat3-deficient cells partially reversed the MT and migration deficiencies. Recombinant Stat3 was also capable of reversing stathmin inhibition of tubulin polymerization in vitro. Our results indicate that Stat3 modulates the MT network by binding to the COOH-terminal tubulin-interacting domain of stathmin and antagonizing its MT destabilization activity.

Signal transducer and activator of transcription 3 (Stat3) is a latent cytoplasmic transcription factor that can be activated by cytokines and growth factors. Stat3 plays important roles in cell growth, anti-apoptosis and cell transformation, and is constitutively active in various cancers. We examined its potential regulators by yeast two-hybrid screening. GRIM-19, a gene product related to interferon-beta- and retinoic acid-induced cancer cell death, was identified and demonstrated to interact with Stat3 in various cell types. The interaction is specific for Stat3, but not for Stat1 and Stat5a. The interaction regions in both proteins were mapped, and the cellular localization of the interaction was examined. GRIM-19 itself co-localizes with mitochondrial markers, and forms aggregates at the perinulear region with co-expressed Stat3, which inhibits Stat3 nuclear translocation stimulated by epidermal growth factor (EGF). GRIM-19 represses Stat3 transcriptional activity and its target gene expression, and also suppresses cell growth in Src-transformed cells and a Stat3-expressing cell line. Our data suggest that GRIM-19 is a novel negative regulator of Stat3.

Egr-l is an immediate-early response gene induced by diverse signals that initiate growth and differentiation. Its cDNA sequence predicts a protein with zinc fingers. We have generated an antiserum to the Egr-1 gene product and identified it as an 80-kilodalton short-lived protein in serum-stimulated mouse fibroblasts. The rat Egr-l product has also been identified in nerve growth factor-induced PC12 cells. In addition, we show by cell fractionation and immunocytochemistry that the Egr-l protein is located in the nucleus. We also demonstrate that it is phosphorylated. In vitro-generated Egr-l protein binds with high affinity to the sequence CGCCCCCGC in a zinc-dependent manner.

Stat3 is activated by phosphorylation on Tyr-705, which leads to dimer formation, nuclear translocation, and regulation of gene expression. Serine phosphorylation of Stat3 by mitogen-activated protein kinase has also been observed in cells responding to epidermal growth factor and shown to affect its tyrosine phosphorylation and transcriptional activity. Serine phosphorylation of Stat3 is also induced by interleukin-6 (IL-6) stimulation, which is shown to be independent of mitogen-activated protein kinase and sensitive to the Ser/ Thr kinase inhibitor H7. In this study, we investigated whether protein kinase C (PKC) is the kinase that is induced and responsible for Stat3 serine phosphorylation by IL-6 stimulation and which isoform of PKCs is likely to be involved. Here, we report that Stat3 was specifically associated with PKC ␦ in vivo in an IL-6-dependent manner in several cell types. Furthermore, Stat3 was phosphorylated by PKC ␦ in vivo on Ser-727, which could be inhibited either by a specific PKC ␦ inhibitor or by a dominant-negative mutant of PKC ␦. Finally, we showed that the phosphorylation of Stat3 by PKC ␦ led to a negative regulation of Stat3 DNA binding and transcriptional activity. These results indicate that PKC ␦ is likely to be the kinase that phosphorylates Stat3 in response to IL-6 stimulation and suggest a possible regulatory role of PKC ␦ on Stat3 function.