A family of p160 coactivators was initially identified based on ligand-dependent interactions with nuclear receptors and thought to function, in part, by recruiting CREB-binding protein͞ p300 to several classes of transcription factors. One of the p160 factors, p͞CIP͞AIB1, often amplified and overexpressed in breast cancer, also exhibits particularly strong interaction with CREBbinding protein͞p300. In this manuscript, we report that p͞CIP, which exhibits regulated transfer from cytoplasm to nucleus, is required for normal somatic growth from embryonic day 13.5 through maturity. Our data suggest that a short stature phenotype of p͞CIP gene-deleted mice reflect both altered regulation of insulin-like growth factor-1 (IGF-1) gene expression in specific tissues and a cell-autonomous defect of response to IGF-1, including ineffective transcriptional activities by several classes of regulated transcription factors under specific conditions. The actions of p͞CIP are therefore required for full expression of a subset of genes critical for regulating physiological patterns of somatic growth in mammals. N uclear receptors comprise a family of transcription factors that regulate gene expression in a ligand-dependent manner and include receptors for steroid hormones, such as estrogen and glucocorticoid, receptors for nonsteroidal ligands, such as thyroid hormone receptor and retinoic acid receptor, as well as receptors that bind diverse products of lipid metabolism (reviewed in refs. 1-5). A combination of genetic, biochemical, and functional data suggests that many factors, including the BRG (Swi͞Snf) complex (6), CREB-binding protein (CBP)͞p300, p160 factors, p͞CAF, and the TRAP͞DRIP͞ARC (7, 8) complex are likely to be critical regulators for at least subsets of nuclear receptor-regulated genes (9-15). However, by the simple criteria of ligand-dependent binding and the ability to synergize on cotransfection assays, numerous additional proteins have been suggested to exert coactivator roles (4, 5).Proteins of approximately 160 kDa molecular mass were among the first factors identified that interact with nuclear receptor in a highly ligand-dependent manner both in solution (16, 17) and on DNA (18) and could themselves associate with CBP (11, 12). Expression cloning and yeast two-hybrid screening approaches led to the identification of three related genes that encode these p160 factors, referred to as SRC-1͞NCoA-1, TIF2͞GRIP-1͞NCoA2, and p͞CIP͞AIB1͞ACTR͞RAC3͞ TRAM-1 (11,(19)(20)(21)(22)(23)(24)(25). These factors bind to nuclear receptors by interactions of LXXLL motif-containing helices within the interaction domain formed by conserved residues in helix3 and helix12 of the liganded receptor (5).Members of the p160 family of nuclear receptor coactivators contain a highly conserved N-terminal bHLH-PAS domain that is also present in members of the Per͞Arnt͞Sim family of transcription factors and mediates protein-protein interactions. Although several lines of evidence support the idea that p160 factors play important roles as...

Background: An inverse relationship between physical activity (PA) and depression among adolescents has been reported in developed communities without consideration of sedentary behaviors (SB, including sitting for course study, viewing TV, and sleeping). We explored the association between recreational PA time (hr/wk) and depression after adjustment with SB and other possible confounders among Chinese adolescents.

Tolerance to morphine-induced analgesia is an intractable phenomenon, often hindering its prolonged applications in the clinics. The enhanced pronociceptive actions of spinal pain-related molecules such as calcitonin gene-related peptide (CGRP) may underlie this phenomenon and could be a promising target for intervention. We demonstrate here how CGRP regulates the development of morphine analgesic tolerance at the spinal level. A 7-day treatment with morphine led to tolerance to its analgesic effects and enhanced expression of CGRP and its receptor subunits calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1). Activation of several cell-type-specific kinase transcription factor cascades is required to mediate this tolerance, including calcium/calmodulin-dependent protein kinase II (CaMKII) and cAMP response element-binding protein (CREB) in neurons, p38 and nuclear factor kappa B (NFκB) in microglia and extracellular signal-regulated protein kinase (ERK) and signal transducer and activator of transcription 1 and 3 (Stat1/3) in astrocytes, because inhibitors of CaMKII, p38 and ERK pathways correspondingly reduced the increases in phosphorylated CREB, acetylated-NFκB and phosphorylated Stat1/3 levels and attenuated the development of tolerance. Interestingly, these cascades were linked to the regulation of glutamatergic N-methyl-d-aspartate (NMDA) receptor expression. Chronic morphine-induced behavioural responses and biochemical events were all subjugated to modulation by disrupting CGRP receptor signaling. Together, these data suggest that CGRP contributes to the development of tolerance to morphine-induced analgesia by regulating the activation of the neuronal CaMKII-CREB, microglial p38-NFκB and astroglial ERK-Stat1/3 cascades. Targeting CGRP-associated signaling molecules may prolong or restore morphine's analgesic properties upon a chronic exposure.

Background:Childhood obesity has been becoming a worldwide public health problem. We conducted a community-based physical activity (PA) intervention program aiming at childhood obesity prevention in general student population in Nanjing of China, the host city of the 2nd World Summer Youth Olympic Games (YOG-Obesity study).Methods:This was a cluster randomized controlled intervention study. Participants were the 4th (mean age±s.e.: 9.0±0.01) and 7th (mean age±s.e.: 12.0±0.01) grade students (mean age±s.e.: 10.5±0.02) from 48 schools and randomly allocated (1:1) to intervention or control groups at school level. Routine health education was provided to all schools, whereas the intervention schools additionally received an 1-year tailored multi-component PA intervention program, including classroom curricula, school environment support, family involvement and fun programs/events. The primary outcome measures were changes in body mass index, obesity occurrence and PA.Results:Overall, 9858 (97.7%) of the 10091 enrolled students completed the follow-up survey. Compared with the baseline, PA level increased by 33.13 min per week (s.e. 10.86) in the intervention group but decreased by 1.76 min per week (s.e. 11.53) in the control group (P=0.028). After adjustment for potential confounders, compared with the control group, the intervention group were more likely to have increased time of PA (adj. Odds ratio=1.15, 95% confidence interval=1.06–1.25), but had a smaller increase in mean body mass index (BMI) (0.22 (s.e. 0.02) vs 0.46 (0.02), P=0.01) and BMI z-score (0.07 (0.01) vs 0.16 (0.01), P=0.01), and were less likely to be obese (adj. Odds ratio=0.7, 95% confidence interval=0.6, 0.9) at study end. The intervention group had fewer new events of obesity/overweight but a larger proportion of formerly overweight/obese students having normal weight by study end.Conclusions:This large community-based PA intervention was feasible and effective in promoting PA and preventing obesity among the general student population in a large city in China. Experiences from this study are the lessons for China to control the childhood obesity epidemic.

The role of mitofusin 2 (MFN2), a key regulator of mitochondrial morphology and function in the renal stress response is unknown. To assess its role, the MFN2 floxed gene was conditionally deleted in the kidney of mice (MFN2 cKO) by Pax2 promoter driven Cre expression (Pax2Cre). MFN2 cKO caused severe mitochondrial fragmentation in renal epithelial cells that are critical for normal kidney tubular function. However, despite a small (20%) decrease in nephron number, newborn cKO pups had organ or tubular function that did not differ from littermate Cre-negative pups. MFN2 deficiency in proximal tubule epithelial cells in primary culture induced mitochondrial fragmentation but did not significantly alter ATP turnover, maximal mitochondrial oxidative reserve capacity, or the low level of oxygen consumption during cyanide exposure. MFN2 deficiency also did not increase apoptosis of tubule epithelial cells under non-stress conditions. In contrast, metabolic stress caused by ATP depletion exacerbated mitochondrial outer membrane injury and increased apoptosis by 80% in MFN2 deficient vs. control cells. Despite similar stress-induced Bax 6A7 epitope exposure in MFN2 deficient and control cells, MFN2 deficiency significantly increased mitochondrial Bax accumulation and was associated with greater release of both apoptosis inducing factor and cytochrome c. In conclusion, MFN2 deficiency in the kidney causes mitochondrial fragmentation but does not affect kidney or tubular function during development or under non-stress conditions. However, MFN2 deficiency exacerbates renal epithelial cell injury by promoting Bax-mediated mitochondrial outer membrane injury and apoptosis.

Pituitary tumor transforming gene (PTTG) is a newly identified transforming gene, the functional mechanism of which is little understood. Computational analysis reveals a C terminus rich in Glu and Pro, a known characteristic of transcriptional activation domains. We report here that murine PTTG indeed possesses transactivation ability, which correlates highly with its transforming properties. residue not only disrupted the transactivation function but also resulted in the loss of transforming ability in NIH3T3 cells. A murine PTTG cDNA that encodes a variant C-terminal tail (Gly-Lys-Gly-Val-Arg-Ser-Asn-Gly-Cys-Lys-Asp-LeuVal-Thr) was cloned. This novel PTTG is devoid of transactivation and transforming ability; deletion of its variant C-terminal tail restores both transactivation and transforming ability. These results show a high correlation between the transforming and transactivation functions of PTTG and also indicate that the novel PTTG variant may function as an endogenous competitor to wild-type PTTG.Oncogenes, under certain conditions, affect cellular controls of proliferation, death, migration, and adhesion leading to neoplastic transformation. Many overexpressed oncogenes such as Ras possess the ability to transform NIH3T3 cells in vitro (1). Pituitary tumor transforming gene (PTTG), 1 recently isolated by our laboratory (2), encodes a novel 199-amino acid protein with no significant similarity to known proteins. Overexpression of rat PTTG in NIH3T3 fibroblasts induced cellular transformation in vitro, and injection of PTTG-transfected 3T3 cells into athymic nude mice generated tumors, indicating the transforming properties of PTTG (2). The human homologue of rat PTTG (hPTTG) has also been identified (3), and its overexpression in 3T3 cells resulted in increased expression of basic fibroblast growth factor-2, a potent angiogenic growth factor (3). PTTG has also been found to participate in early stage development of prolactinoma and is highly expressed in experimental and clinical pituitary tumors (4, 5). PTTG recently was shown to behave as a vertebrate sister-chromatid separation inhibitor providing a potential mechanism for PTTG to mediate aneuploidy and genetic instability, thus contributing to cell malignancy (6).Human PTTG has several gene homologues comprising a gene family including PTTG1 (most homologous to rat PTTG), PTTG2, PTTG3, and PTTG4 (7). We have also cloned the murine PTTG cDNA (most homologous to human PTTG1) and its promoter (8). In a detailed computational analysis of human, rat, and murine PTTG protein sequences, Glu and Pro residues were observed to be abundant in the C-terminal region, a known characteristic of transactivation domains in transcription factors and/or co-activators. We therefore fused murine PTTG with a GAL4 DNA binding domain and found that PTTG indeed possesses transcriptional activation ability; mutation analysis identified several residues and regions important for this activation, and soft agar assay suggested a high correlation between transactivating and t...

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Although many epidemiological studies have investigated the association between body mass index (BMI) and risk of rheumatoid (RA), the results have been inconsistent. Therefore, we performed a dose-response meta-analysis to quantify the dose-response association between BMI and RA risk.We systematically searched PubMed, Embase, and Web of Science databases and reference lists of articles for relevant studies published before August 2014 using terms related to BMI and RA. Fixed or random-effects models were used to estimate the pooled relative risk (RR) with 95% confidence interval (CI). Several subgroup analyses, sensitivity analyses, and publication bias tests were performed to explore potential study heterogeneity and biasThirteen studies involving 400,609 participants and 13,562 RA cases were included. The RR of RA was 1.21 (95% CI: 1.02–1.44) for obesity, 1.05 (95% CI: 0.97–1.13) for overweight. The risk of RA increased by 13% (RR: 1.13; 95% CI: 1.01–1.26) for every 5 kg/m2 increase in BMI. The subgroup analyses showed a positive association between BMI and RA risk only in women with an RR of 1.26 (95% CI: 1.12–1.40) for obesity and 1.12(95% CI: 1.07–1.18) for every 5 kg/m2 increase in BMI. Also, an increased risk of RA was found in sero-negative subgroup with an RR of 1.47 (95% CI: 1.11–1.96) for obesity and 1.21 (95% CI: 1.06–1.39) for every 5 kg/m2 increase in BMI.There is evidence that obesity is a risk factor for developing of RA. Furthermore, the positive association between BMI and RA risk may be stronger among women than men.