👤 Xueyang Zong

Recent large-scale genome-wide association studies have identified multiple loci robustly associated with BMI, predominantly in European ancestry (EA) populations. However, associations of these loci with obesity and related traits have not been well described in Chinese Hans. This study aimed to investigate whether BMI-associated loci are, individually and collectively, associated with adiposity-related traits and obesity in Chinese Hans and whether these associations are modified by physical activity (PA). We genotyped 28 BMI-associated single nucleotide polymorphisms (SNPs) in a population-based cohort including 2,894 unrelated Han Chinese. Genetic risk score (GRS), EA and East Asian ancestry (EAA) GRSs were calculated by adding BMI-increasing alleles based on all, EA and EAA identified SNPs, respectively. Interactions of GRS and PA were examined by including the interaction-term in the regression model. Individually, 26 of 28 SNPs showed directionally consistent effects on BMI, and associations of four loci (TMEM18, PCSK1, BDNF and MAP2K5) reached nominal significance (P<0.05). The GRS was associated with increased BMI, trunk fat and body fat percentages; and increased risk of obesity and overweight (all P<0.05). Effect sizes (0.11 vs. 0.17 kg/m2) and explained variance (0.90% vs. 1.45%) of GRS for BMI tended to be lower in Chinese Hans than in Europeans. The EA GRS and EAA GRS were associated with 0.11 and 0.13 kg/m2 higher BMI, respectively. In addition, we found that PA attenuated the effect of the GRS on BMI (Pinteraction = 0.022). Our observations suggest that the combined effect of obesity-susceptibility loci on BMI tended to be lower in Han Chinese than in EA. The overall, EA and EAA GRSs exert similar effects on adiposity traits. Genetic predisposition to increased BMI is attenuated by PA in this population of Han Chinese. Show less

Little is known about the associations of FADS1 genetic variants with circulating levels of PUFA and lipids in Asian populations who have a different dietary pattern and dyslipidemia prevalence compared with Western populations. In a population-based sample of 3,210 unrelated Han Chinese living in Beijing and Shanghai, we examined a FADS1 genetic variant, rs174550, in relation to blood PUFA and lipid levels. C-allele of rs174550 was significantly associated with levels of erythrocyte PUFAs in upstream and downstream pathways of delta-5 desaturase (D5D) (P ≤ 0.003). Moreover, rs174550 C-allele was associated with a lower HDL cholesterol level (P = 0.02) in total population and a higher triglyceride level (P = 0.0002) in Beijing residents. Interestingly, erythrocyte levels of 18:2n-6 and 18:3n-3 modified the effect of rs174550 on HDL cholesterol level: stronger associations between rs174550 C-allele and lower HDL cholesterol levels were exhibited when erythrocyte 18:2n-6 or 18:3n-3 level was low (P for interaction = 0.02 and 0.03, respectively). These data suggested that FADS1 genetic variant was associated with circulating PUFA and lipid levels and that its effect on HDL cholesterol might depend on PUFA status in the Han Chinese population. Show less

We aimed to assess the biologic activity of PF-03084014 in breast xenograft models. The biomarkers for mechanism and patient stratification were also explored. The in vitro and in vivo properties of PF-03084014 were investigated. The mRNA expressions of 40 key Notch pathway genes at baseline or after treatment were analyzed to link with the antitumor efficacy of PF-03084014 in a panel of breast cancer xenograft models. In vitro, PF-03084014 exhibited activity against tumor cell migration, endothelial cell tube formation, and mammosphere formation. In vivo, we observed apoptosis, antiproliferation, reduced tumor cell self-renewal ability, impaired tumor vasculature, and decreased metastasis activity after the treatment of PF-03084014. PF-03084014 treatment displayed significant antitumor activity in 10 of the 18 breast xenograft models. However, the antitumor efficacy in most models did not correlate with the in vitro antiproliferation results in the corresponding cell lines, suggesting the critical involvement of tumor microenvironment during Notch activation. In the tested breast xenograft models, the baseline expressions of the Notch receptors, ligands, and the cleaved Notch1 failed to predict the antitumor response to PF-03084014, whereas several Notch pathway target genes, including HEY2, HES4, and HES3, strongly corresponded with the response with a P value less than 0.01. Many of the best molecular predictors of response were also significantly modulated following PF-03084014 treatment. PF-03084014 showed antitumor and antimetastatic properties via pleiotropic mechanisms. The Notch pathway downstream genes may be used to predict the antitumor activity of PF-03084014 and enrich for responders among breast cancer patients. Show less

PIK3C3/Vps34 is the class III PtdIns3K that is evolutionarily conserved from yeast to mammals. Its central role in mammalian autophagy has been suggested through the use of pharmacological inhibitors and the study of its binding partners. However, the precise role of PIK3C3 in mammals is not clear. Using mouse strains that allow tissue-specific deletion of PIK3C3, we have described an essential role of PIK3C3 in regulating autophagy, and liver and heart function. Show less

A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34(f/f) mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34(f/f) mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function. Show less

A 1933 bp cDNA fragment, coding a truncated testis-specific novel nucleoporin, was isolated from a human testis lambdaZAPII cDNA library, designated as BS-63 and assigned GenBank accession number: U64675. By applying the methods of rapid amplification of cDNA ends (5' RACE) and PCR, a full-length BS-63 cDNA composed of 5475 bp was obtained. BS-63 cDNA contained an open reading frame consisting of 1765 codons and XFXFG or GLFG repetitive sequence motifs. These repetitive motifs are structural characteristic of nucleoporins. BS-63 cDNA has high homology with Nup358/Ran BP2. A 1599 bp fragment, corresponding to the C-terminus of BS-63 cDNA, was prepared and expressed in E. coli BL21(DE3). The recombinant product was purified by affinity chromatography and SDS-PAGE and polyclonal antibodies raised. In rat testis section, the BS-63 protein was localized at the sites of nuclear pores in spermatids by immuno-gold transmission electron microscopy and on the nuclear membrane of Triton X-treated sperm by colloidal silver immuno-gold scanning electron microscopy. The recombinant BS-63 protein can be phosphorylated in vitro with PKC and p34(cdc2). A yeast two-hybrid system was used to screen a mouse testis cDNA library to identify proteins capable of interacting with BS-63. Using the 1.6 kb cDNA fragment as bait, the following interacting proteins were identified: Ran, transportin (karyopherin beta2), two proteins related to the nucleocytoplasmic transporter and aF10 protein. The latter protein is a putative transcriptor containing a cysteine-rich N-terminus, a LAP/PHD finger, a leucine zipper domain and a glutamine-rich C-terminus. Also it is highly expressed in murine testis and is located in the cell nucleus and cytoplasm. The interaction of BS-63 with aF10 (696-1001aa) was validated by surface plasmon resonance and by affinity precipitation combined with Western blot. aF10 (696-1001aa) interacted in vitro with BS-63 extracted from rat testis germ cells. It is hypothesized that BS-63 is a testis-specific nucleoporin and possibly acts as a docking site and a cotransporter of Ran and transportin. The complex performs the task of a carrier system in transporting aF10 into the nucleus of germ cells during spermiogenesis. Show less

The association of G(1) cyclins and Cdc28/cyclin-dependent protein kinase catalyzes the cell cycle entry (Start) in budding yeast. Activation of Start is presumed to be triggered by a post-transcriptional increase in Cln3 during early G(1). Cells arrested by mating pheromone show a loss of cyclin-dependent protein kinase activity caused by transcriptional shutoff of cyclins and/or inhibition by Far1. We report that overexpression of eIF4E (Cdc33), a rate-limiting translation initiation factor, causes an increase in CLN3 mRNA translation, which results in increased expression of CLN2 and in slow growth and decreased alpha-factor response. This phenotype was abrogated in a Deltacln3 or Deltacln2 background. We isolated the transcription factor MBP1 as a multicopy suppressor of the growth and alpha-factor response defects. Furthermore, elevated MBP1, a transcriptional regulator of cyclins, altered the transcriptional start site in CLN3 mRNA, shifting it 45 nucleotides upstream of the normal. This lengthened 5'-untranslated region likely reduces translation efficiency and down-regulates CLN3 protein synthesis, thereby correcting for the excess translation promoted by elevated Cdc33. In addition, the CLN2 mRNA level returned to normal. We propose that regulation of translation initiation by Cdc33 plays a pivotal role in the activation of Start and cell cycle progression in budding yeast. Show less