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Articles by W Li
Total Records ( 22 ) for W Li
  Q Qiu , G Liu , W Li , Q Shi , F Zhu and G. Lu

Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first committed step of de novo triacylglycerol synthesis by converting glycerol-3-phosphate to lysophosphatidic acid (LPA). LPA is a mitogen that mediates multiple cellular processes including cell proliferation. Four GPAT isoforms have been cloned to date. GPAT4 is strongly expressed in the mouse testis. Reverse transcription–polymerase chain reaction (PCR), real-time PCR, and in situ hybridization (ISH) were used to analyze the GPAT4 expression and to localize the expressing cell types in the mouse testis during postnatal development. GPAT4 cDNA was inserted into pcDNA4/His to construct a recombinant vector, which was transfected into a mouse spermatogonial cell line (GC-1spg). GPAT4 was first expressed in mice at 2 weeks postnatally. Expression was abundant from the third week, plateaued at week 5–6 and then maintained at a high level in the adult. ISH revealed that GPAT4 gene was expressed abundantly in spermatocytes and around spermatids during meiosis but not in elongated spermatids during later spermiogenesis. GC-1spg cells showed a marked increase in proliferation after transfection with GPAT4; cell cycle analysis showed a decrease in the percentage of cells in the G0/G1 phase and an increase in the S phase. Thus, GPAT4 might play an important role in spermatogenesis, especially in mid-meiosis.

  B Xiang , M Yi , L Wang , W Liu , W Zhang , J Ouyang , Y Peng , W Li , M Zhou , H Liu , M Wu , R Wang , X Li and G. Li

Oxidored-nitro domain containing protein 1 (NOR1) gene is a novel nitroreductase gene first isolated from nasopharyngeal carcinoma (NPC). It plays an important role in the formation of chemical carcinogen and the carcinogenesis of NPC for its nitrosation function. Overexpression of the wild-type NOR1 gene in nasopharyngeal carcinoma cells is effective to inhibit cell growth and proliferation. In this study, for the first time, we generated a highly specific NOR1 antibody and analyzed NOR1 distribution in the human tissues and NPC biopsies. The results showed that NOR1 protein is predominantly expressed in human nasopharynx and tracheal tissues. Human heart, liver, spleen, stomach, colon, kidney, skeletal muscle, thymus, and pancreas are all deficient of NOR1 protein. More importantly, we performed immunohistochemistry assay of NOR1 protein expression in the NPC tissues, and the result showed that NOR1 protein is frequently down-expressed in NPC. These data shed light on the selectivity of potential physiological functions of NOR1 and provides an indispensable reference to the carcinogenesis process of NPC and to identify or validate tissue-specific drug targets.

  W Li , B Zhao , Y Jin and K. Ruan

MicroRNA (miRNA) microarray is a powerful tool to explore the expression profiling of miRNA. The current detection method used in miRNA microarray is mainly fluorescence based, which usually requires costly detection system such as laser confocal scanner of tens of thousands of dollars. Recently, we developed a low-cost yet sensitive detection method for miRNA microarray based on enzyme-linked assay. In this approach, the biotinylated miRNAs were captured by the corresponding oligonucleotide probes immobilized on microarray slide; and then the biotinylated miRNAs would capture streptavidin-conjugated alkaline phosphatase. A purple-black precipitation on each biotinylated miRNA spot was produced by the enzyme catalytic reaction. It could be easily detected by a charge-coupled device digital camera mounted on a microscope, which lowers the detection cost more than 100 fold compared with that of fluorescence method. Our data showed that signal intensity of the spot correlates well with the biotinylated miRNA concentration and the detection limit for miRNAs is at least 0.4 fmol and the detection dynamic range spans about 2.5 orders of magnitude, which is comparable to that of fluorescence method.

  P Jiang , J Liu , W Li , X Zeng and J. Tang

The objective of this study was to identify whether polymorphic variants of p53 at codon 72 and p21 at codon 31 were associated with increased risk for cervical cancer, either independently or jointly, among Chinese women from southern Han. We genotyped p53 codon 72 and p21 codon 31 polymorphisms of peripheral blood DNA from 104 cervical cancer patients and 160 controls. Genotyping was confirmed by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and direct DNA sequencing. We observed an increased risk of cervical cancer associated with the p53 Arg/Arg (OR, 2.25; 95% CI, 1.11–4.54) or p21 Ser/Ser (OR, 2.09; 95% CI, 1.04–4.19) genotype, compared with the p53 Pro/Pro or p21 Arg/Arg genotype, respectively. In additional, interaction between these p53 and p21 polymorphisms increased the risk of cervical cancer in a multiplicative manner, with the OR being 3.96 (95% CI, 1.51–10.41) for subjects carrying both p53 Arg/Arg and p21 Ser/Ser genotypes. These findings suggest that there is a significant association between the genetic polymorphism of p53, p21, and the risk of cervical cancer among Chinese southern women, and there is a possible gene–gene interaction in the incidence of cervical cancer.

  W Li , C Wang , S. K Juhn , F. G Ondrey and J. Lin

Objectives  To characterize the expression of fibroblast growth factor binding protein (FGF-BP) messenger RNA (mRNA) in head and neck squamous cell carcinoma (HNSCC) and to study the association of FGF-BP with vascularity.

Design  The expression of FGF-BP mRNA in HNSCC was studied in 35 primary and 8 metastatic HNSCC specimens and 7 control tissues using in situ hybridization and reverse transcriptase–polymerase chain reaction (RT-PCR). Microvessels in tumor specimens were identified with endothelial cell markers (von Willebrand factor [vWF] and CD34-specific antibodies). Correlates between FGF-BP and microvessel counts were evaluated statistically.

Setting  University of Minnesota Hospitals and Clinics.

Patients  Forty-two surgically treated patients with HNSCC.

Interventions  The patients were routinely treated in the study hospitals and clinics.

Main Outcome Measures  The expression of FGF-BP and angiogenesis in tumors were evaluated.

Results  In situ hybridization and RT-PCR demonstrated that FGF-BP mRNA transcripts were expressed in 34 of 35 primary HNSCC specimens and 5 of 8 metastatic tumor specimens but not in adjacent control tissues. The microvessel counts in HNSCC specimens were closely related to the expression level of FGF-BP (P < .001).

Conclusion  The expression of FGF-BP is statistically linked to the angiogenesis of HNSCC, suggesting that FGF-BP participates in the angiogenesis of HNSCC.

  Z Han , Z Hong , C Chen , Q Gao , D Luo , Y Fang , Y Cao , T Zhu , X Jiang , Q Ma , W Li , L Han , D Wang , G Xu , S Wang , L Meng , J Zhou and D. Ma

Tumor cells acquire the ability to proliferate uncontrollably, resist apoptosis, sustain angiogenesis and evade immune surveillance. Signal transducer and activator of transcription (STAT) 3 regulates all of these processes in a surprisingly large number of human cancers. Consequently, the STAT3 protein is emerging as an ideal target for cancer therapy. This paper reports the generation of an oncolytic adenovirus (M4), which selectively blocks STAT3 signaling in tumor cells as a novel therapeutic strategy. M4 selectively replicated in tumor cells and expressed high levels of antisense STAT3 complementary DNA during the late phase of the viral infection in a replication-dependent manner. The viral progeny yield of M4 in tumor cells was much higher than that of the parent adenoviral mutants, Ad5/dE1A. M4 effectively silenced STAT3 and its target genes in tumor cells while sparing normal cells and exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M4 significantly inhibited tumor growth in an orthotopic gastric carcinoma mouse model, eliminated abdominal cavity metastases and prolonged survival time. In summary, M4 has low toxicity and great potential as a therapeutic agent for different types of cancers.

  M. S Maron , B. M Kalsmith , J. E Udelson , W Li and D. DeNofrio

Heart transplant is a treatment option for selected patients with hypertrophic cardiomyopathy (HCM). However, the prevalence, clinical profile, and outcome of this subgroup of HCM patients are uncertain. Therefore, we sought to determine the occurrence, clinical characteristics, and prognosis of HCM patients who underwent cardiac transplantation in the United States during a 15-year period.

Methods and Results—

Demographic, clinical, and survival outcomes of 26 706 adult (age ≥18 years), heart-only transplant recipients between January 1990 and December 2004 were acquired from the United Network of Organ Sharing Registry. Pretransplant diagnoses were classified as follows: HCM (n=303, 1%) and non-HCM (26 403, 99%), comprising 3 patient subgroups: (1) ischemic cardiomyopathy (n=14 308, 54%), (2) dilated cardiomyopathy (n=11 760, 44%), and (3) restrictive cardiomyopathy (n=335, 1%). Study follow-up began at the time of heart transplant and was 76±44 months (mean±SD) among survivors. The 1-, 5-, and 10-year overall transplant survival for HCM patients was 85%, 75%, and 61%, respectively, with a trend toward greater survival compared with that of non-HCM transplant patients (82%, 70%, and 49%, respectively; log-rank test, P=0.05). However, propensity-matched, covariate-adjusted, Cox regression model analysis showed better survival over time (P<0.01) among the HCM patients. When HCM posttransplant survival was compared with that in each of the non-HCM patient subgroups, HCM patients had more favorable survival than did those transplanted for ischemic cardiomyopathy (P=0.02). In contrast, HCM posttransplant survival did not differ from that of patients transplanted for restrictive (P=0.08) or dilated (P=0.25) cardiomyopathy.


HCM patients compose a small subset (1%) of the overall population of patients who undergo heart transplantation in the United States. Nonetheless, survival after transplant among HCM patients is comparable to that of patients transplanted for non-HCM cardiovascular diseases, with possible enhanced survival over time.

  W Li , W Zou , D Zhao , J Yan , Z Zhu , J Lu and X. Wang
  Weida Li, Wei Zou, Dongfeng Zhao, Jiacong Yan, Zuoyan Zhu, Jing Lu, and Xiaochen Wang

During apoptosis, dying cells are quickly internalized by neighboring cells or phagocytes, and are enclosed in phagosomes that undergo a maturation process to generate the phagoslysosome, in which cell corpses are eventually degraded. It is not well understood how apoptotic cell degradation is regulated. Here we report the identification and characterization of the C. elegans tbc-2 gene, which is required for the efficient degradation of cell corpses. tbc-2 encodes a Rab GTPase activating protein (GAP) and its loss of function affects several events of phagosome maturation, including RAB-5 release, phosphatidylinositol 3-phosphate dynamics, phagosomal acidification, RAB-7 recruitment and lysosome incorporation, which leads to many persistent cell corpses at various developmental stages. Intriguingly, the persistent cell corpse phenotype of tbc-2 mutants can be suppressed by reducing gene expression of rab-5, and overexpression of a GTP-locked RAB-5 caused similar defects in phagosome maturation and cell corpse degradation. We propose that TBC-2 functions as a GAP to cycle RAB-5 from an active GTP-bound to an inactive GDP-bound state, which is...

  X Wang , Y. P Hsueh , W Li , A Floyd , R Skalsky and J. Heitman

Cosuppression is a silencing phenomenon triggered by the introduction of homologous DNA sequences into the genomes of organisms as diverse as plants, fungi, flies, and nematodes. Here we report sex-induced silencing (SIS), which is triggered by tandem integration of a transgene array in the human fungal pathogen Cryptococcus neoformans. A SXI2a-URA5 transgene array was found to be post-transcriptionally silenced during sexual reproduction. More than half of the progeny that inherited the SXI2a-URA5 transgene became uracil-auxotrophic due to silencing of the URA5 gene. In vegetative mitotic growth, silencing of this transgene array occurred at an ~250-fold lower frequency, indicating that silencing is induced during the sexual cycle. Central components of the RNAi pathway—including genes encoding Argonaute, Dicer, and an RNA-dependent RNA polymerase—are all required for both meiotic and mitotic transgene silencing. URA5-derived ~22-nucleotide (nt) small RNAs accumulated in the silenced isolates, suggesting that SIS is mediated by RNAi via sequence-specific small RNAs. Through deep sequencing of the small RNA population in C. neoformans, we also identified abundant small RNAs mapping to repetitive transposable elements, and these small RNAs were absent in rdp1 mutant strains. Furthermore, a group of retrotransposons was highly expressed during mating of rdp1 mutant strains, and an increased transposition/mutation rate was detected in their progeny, indicating that the RNAi pathway squelches transposon activity during the sexual cycle. Interestingly, Ago1, Dcr1, Dcr2, and Rdp1 are translationally induced in mating cells, and Ago1, Dcr1, and Dcr2 localize to processing bodies (P bodies), whereas Rdp1 appears to be nuclear, providing mechanistic insights into the elevated silencing efficiency during sexual reproduction. We hypothesize that the SIS RNAi pathway operates to defend the genome during sexual development.

  W Li and J. Freudenberg

The genome-wide recombination rate (RR) of a species is often described by one parameter, the ratio between total genetic map length (G) and physical map length (P), measured in centimorgans per megabase (cM/Mb). The value of this parameter varies greatly between species, but the cause for these differences is not entirely clear. A constraining factor of overall RR in a species, which may cause increased RR for smaller chromosomes, is the requirement of at least one chiasma per chromosome (or chromosome arm) per meiosis. In the present study, we quantify the relative excess of recombination events on smaller chromosomes by a linear regression model, which relates the genetic length of chromosomes to their physical length. We find for several species that the two-parameter regression, G = G0 + k · P , provides a better characterization of the relationship between genetic and physical map length than the one-parameter regression that runs through the origin. A nonzero intercept (G0) indicates a relative excess of recombination on smaller chromosomes in a genome. Given G0, the parameter k predicts the increase of genetic map length over the increase of physical map length. The observed values of G0 have a similar magnitude for diverse species, whereas k varies by two orders of magnitude. The implications of this strategy for the genetic maps of human, mouse, rat, chicken, honeybee, worm, and yeast are discussed.

  Y Hao , L Li , W Li , X Zhou and J. Lu

Bacterial virulence could be altered by the antimicrobial agents of the host. Our aim was to identify the damage and survival of Streptococcus sanguinis induced by lysozymes in vitro and to analyse the potential of oral microorganisms to shirk host defences, which cause infective endocarditis. S. sanguinis ATCC 10556 received lysozyme at concentrations of 12.5, 25, 50 and 100 µg/ml. Cells were examined by electron microscopy. The survival was assessed by colony counting and construction of a growth curve. Challenged by lysozymes, cells mainly exhibited cell wall damage, which seemed to increase with increasing lysozyme concentration and longer incubation period in the presence of ions. Cells with little as well as apparent lesion were observed under the same treatment set, and anomalous stick and huge rotund bodies were occasionally observed. After the removal of the lysozyme, some damaged cells could be reverted to its original form with brain heart infusion (BHI), and their growth curve was similar to the control cells. After further incubation in BHI containing lysozyme, S. sanguinis cell damage stopped progressing, and their growth curve was also similar to the control cells. The results suggested that the S. sanguinis lesions caused by the lysozyme in the oral cavity may be nonhomogeneous and that some damaged cells could self-repair and survive. It also indicated that S. sanguinis with damaged cell walls may survive and be transmitted in the bloodstream.

  X Du , Z Chen , W Li , Y Tan , J Lu , X Zhu , T Zhao , G Dong and L. Zeng

The objectives of this study are to establish microsatellite loci for the Mongolian gerbil based on mouse microsatellite DNA sequences and to investigate genetic variation in the laboratory gerbil (Capital Medical University, CMU) and 2 wild gerbil populations (from Yin Chuan city [YIN] and the Hohehot Municipality [HOH]). In total, 536 mouse microsatellite markers were chosen to identify polymorphic dinucleotide repeat loci in the gerbil by cross-amplification. Of these markers, 313 (58.39%) have been discretely amplified from the CMU laboratory gerbil and been sequenced. Of the 313 sequenced markers, 130 were confirmed as simple sequence repeat (SSR) loci in the gerbil. In total, 6 of those newly identified loci plus 6 identified in previous reports were used to estimate the genetic polymorphism for 30 laboratory gerbils and 54 wild gerbils (27 each of the HOH and YIN groups). A total of 29 alleles were observed in the 3 populations, and 11 of 12 loci (91.67%) are polymorphic markers. Nei's standard genetic distances of 0.0592 (CMU vs. HOH) and 0.1033 (CMU vs. YIN) were observed. The averages of observed versus expected heterozygosity are 0.5231/0.4008, 0.5051/0.3882, and 0.4825/0.3665 for the YIN, HOH, and CMU populations, respectively. These results show that cross-amplification using mouse microsatellite primers is an efficient way to identify gerbil SSR loci. By using these 12 selected markers, we have demonstrated that genetic variation level within the CMU population is higher than that has been reported previously and are comparable with the levels found in 2 wild populations.

  R. B Lanz , Y Bulynko , A Malovannaya , P Labhart , L Wang , W Li , J Qin , M Harper and B. W. O'Malley

The nuclear receptor and bona fide oncogene, steroid receptor coactivator-3 (SRC-3, AIB1), acts as a master transcriptional regulator of breast cancer by transducing growth signals via the estrogen receptor (ER). In this resource paper, we present the genome-wide localization analysis of SRC-3 chromatin affinity sites in MCF-7 human breast cancer chromatin and compare the cis binding sites to global cartographies for ER and FoxA1. By correlating their gene proximal binding sites to integrated gene expression signatures, and in combination with gene ontology analyses, we provide a functional classification of estradiol-induced gene regulation that further highlights an intricate transcriptional control of interdependent cellular pathways by SRC-3. Furthermore, by presenting proteomics analyses of in vivo SRC-3- and ER-associated proteins, we give strong evidence to support the idea that the interpretative power of SRC-3 in estrogen signaling is mediated through the formation of distinct, cell state-dependent protein complexes. Altogether, we present the first approach in complementary comparative analyses that converges results obtained by three discovery-driven methods (cistromics, transcriptomics, and proteomics) into testable hypotheses, thus providing a valuable resource for follow-up studies that further our understanding of estrogen signaling in human diseases in general and breast cancer in particular.

  S Zheng , W Li , M Xu , X Bai , Z Zhou , J Han , J. Y. J Shyy and X. Wang

Ischemia induces angiogenesis as a compensatory response. Although ischemia is known to causes synthesis and release of calcitonin gene-related peptide (CGRP), it is not clear whether CGRP regulates angiogenesis under ischemia and how does it function. Thus we investigated the role of CGRP in angiogenesis and the involved mechanisms. We found that CGRP level was increased in the rat hindlimb ischemic tissue. The expression of exogenous CGRP by adenovirus vectors enhanced blood flow recovery and increased capillary density in ischemic hindlimbs. In vitro, CGRP promoted human umbilical vein endothelial cell (HUVEC) tube formation and migration. Further more, CGRP activated AMP-activated protein kinase (AMPK) both in vivo and in vitro, and pharmacological inhibition of CGRP and cAMP attenuated the CGRP-activated AMPK in vitro. CGRP also induced endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs at Ser1177 and Ser633 in a time-dependent manner, and such effects were abolished by AMPK inhibitor Compound C. As well, Compound C blocked CGRP-enhanced HUVEC tube formation and migration. These findings indicate that CGRP promotes angiogenesis by activating the AMPK-eNOS pathway in endothelial cells.

  G Fan , C Feng , Y Li , C Wang , J Yan , W Li , J Feng , X Shi and Y. Bi

Background: We carried out animal experiments based on the orthogonal design L8(27) setting seven factors with two different levels of each and 10 groups of rats. The nutrients tested were tyrosine, glycine, methionine, taurine, ascorbic acid, thiamine and zinc.

Objectives: The objective of this study was to explore the optimal combinations of nutrients for prevention or amelioration of lead-induced learning and memory impairment.

Methods: Rats were supplemented with nutrients by gavage once a day in two experiments: one was simultaneous nutrient supplementation with lead acetate administration (800 mg l–1) for 8 weeks (prophylactic supplementation) and the other was nutrient supplementation for 4 weeks after the cessation of 4 weeks of lead administration (remedial supplementation). Morris water maze was initiated at ninth week. Rats were terminated for assays of levels of Pb in blood, activities of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in hippocampus, levels of nitric oxide (NO) in hippocampus and expressions of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) response element-binding protein messenger RNA in hippocampus.

Results: Results showed that in prophylactic supplementation, methionine, taurine, zinc, ascorbic acid and glycine were the effective preventive factors for decreasing prolonged escape latency, increasing SOD and NOS activities and NO levels in the hippocampus, respectively. On the other hand, in remedial supplementation, taurine was the effective factor for reversing Pb-induced decrease in activities of SOD, NOS and levels of NO.

Conclusions: In conclusion, the optimum combinations of nutrients appear to be methionine, taurine, zinc, ascorbic acid and glycine for the prevention of learning and memory impairment, while taurine and thiamine appear to be the effective factors for reversing Pb neurotoxicity.

  Y. C Wang , X. B Hu , F He , F Feng , L Wang , W Li , P Zhang , D Li , Z. S Jia , Y. M Liang and H. Han

Dendritic cells (DCs) are professional antigen presenting cells to initiate immune response against pathogens, but mechanisms controlling the maturation of DCs are unclear. Here we report that, in the absence of recombination signal binding protein-J (RBP-J, the transcription factor mediating Notch signaling), lipopolysaccharide-stimulated monocyte-derived DCs are arrested at a developmental stage with few dendrites, low major histocompatibility complex II (MHC II) expression, and reduced motility and antigen presentation ability. RBP-J null DCs had lower expression of CXCR4. Transduction with a CXCR4-expressing lentivirus rescued developmental arrest of RBP-J-deficient DCs. Activation of Notch signaling in DCs up-regulated CXCR4 expression and increased the outgrowth of dendrites and the expression of MHC II. These effects were abrogated by a CXCR4 inhibitor. Therefore, Notch signaling is essential for DCs to transit from a dendritelowMHC IIlow immature state into a dendritehighMHC IIhigh mature state, during the lipopolysaccharide-induced DC maturation, most likely through the up-regulation of CXCR4.

  M. A Esteban , J Xu , J Yang , M Peng , D Qin , W Li , Z Jiang , J Chen , K Deng , M Zhong , J Cai , L Lai and D. Pei

Induced pluripotent stem cell (iPS) technology appears to be a general strategy to generate pluripotent stem cells from any given mammalian species. So far, iPS cells have been reported for mouse, human, rat, and monkey. These four species have also established embryonic stem cell (ESC) lines that serve as the gold standard for pluripotency comparisons. Attempts have been made to generate porcine ESC by various means without success. Here we report the successful generation of pluripotent stem cells from fibroblasts isolated from the Tibetan miniature pig using a modified iPS protocol. The resulting iPS cell lines more closely resemble human ESC than cells from other species, have normal karyotype, stain positive for alkaline phosphatase, express high levels of ESC-like markers (Nanog, Rex1, Lin28, and SSEA4), and can differentiate into teratomas composed of the three germ layers. Because porcine physiology closely resembles human, the iPS cells reported here provide an attractive model to study certain human diseases or assess therapeutic applications of iPS in a large animal model.

  K. E Szulwach , X Li , R. D Smrt , Y Li , Y Luo , L Lin , N. J Santistevan , W Li , X Zhao and P. Jin

The microRNA miR-137 represses expression of Ezh2, a histone methyltransferase, which in turn alters the epigenetic architecture of chromatin that is important for regulation of miR-137 levels.

  I Isomura , S Palmer , R. J Grumont , K Bunting , G Hoyne , N Wilkinson , A Banerjee , A Proietto , R Gugasyan , W Li , A McNally , R. J Steptoe , R Thomas , M. F Shannon and S. Gerondakis

During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-B transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel–/– mice, thymic T reg cell numbers are markedly reduced as a result of a T cell–intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-β conversion of peripheral CD4+CD25 T cells into CD4+Foxp3+ cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripheral T reg cells in c-rel–/– mice, the residual peripheral c-rel–/– T reg cells express normal levels of Foxp3, display a pattern of cell surface markers and gene expression similar to those of wild-type T reg cells, and effectively suppress effector T cell function in culture and in vivo. Collectively, our results indicate that c-Rel is important for both the thymic development and peripheral homeostatic proliferation of T reg cells.

  M Dougan , S Dougan , J Slisz , B Firestone , M Vanneman , D Draganov , G Goyal , W Li , D Neuberg , R Blumberg , N Hacohen , D Porter , L Zawel and G. Dranoff

The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor B (NF-B) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-B2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.

  W Li , D. B Halling , A. W Hall and R. W. Aldrich

Small conductance calcium-activated potassium (SK) channels respond to intracellular Ca2+ via constitutively associated calmodulin (CaM). Previous studies have proposed a modular design for the interaction between CaM and SK channels. The C-lobe and the linker of CaM are thought to regulate the constitutive binding, whereas the N-lobe binds Ca2+ and gates SK channels. However, we found that coexpression of mutant CaM (E/Q) where the N-lobe has only one functional EF hand leads to rapid rundown of SK channel activity, which can be recovered with exogenously applied wild-type (WT), but not mutant, CaM. Our results suggest that the mutation at the N-lobe EF hand disrupts the stable interaction between CaM and SK channel subunits, such that mutant CaM dissociates from the channel complex when the inside of the membrane is exposed to CaM-free solution. The disruption of the stable interaction does not directly result from the loss of Ca2+-binding capacity because SK channels and WT CaM can stably interact in the absence of Ca2+. These findings question a previous conclusion that CaM where the N-lobe has only one functional EF hand can stably support the gating of SK channels. They cannot be explained by the current model of modular interaction between CaM and SK channels, and they imply a role for N-lobe EF hand residues in binding to the channel subunits. Additionally, we found that a potent enhancer for SK channels, 3-oxime-6,7-dichloro-1H-indole-2,3-dione (NS309), enables the recovery of channel activity with CaM (E/Q), suggesting that NS309 stabilizes the interaction between CaM and SK channels. CaM (E/Q) can regulate Ca2+-dependent gating of SK channels in the presence of NS309, but with a lower apparent Ca2+ affinity than WT CaM.

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