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Articles by W Hu
Total Records ( 9 ) for W Hu
  W Hu , S Nessler , B Hemmer , T. N Eagar , L. P Kane , S. R Leliveld , A Muller Schiffmann , A. R Gocke , A Lovett Racke , L. H Ben , R. Z Hussain , A Breil , J. L Elliott , K Puttaparthi , P. D Cravens , M. P Singh , B Petsch , L Stitz , M. K Racke , C Korth and O. Stuve
 

The primary biological function of the endogenous cellular prion protein has remained unclear. We investigated its biological function in the generation of cellular immune responses using cellular prion protein gene-specific small interfering ribonucleic acid in vivo and in vitro. Our results were confirmed by blocking cellular prion protein with monovalent antibodies and by using cellular prion protein-deficient and -transgenic mice. In vivo prion protein gene-small interfering ribonucleic acid treatment effects were of limited duration, restricted to secondary lymphoid organs and resulted in a 70% reduction of cellular prion protein expression in leukocytes. Disruption of cellular prion protein signalling augmented antigen-specific activation and proliferation, and enhanced T cell receptor signalling, resulting in zeta-chain-associated protein-70 phosphorylation and nuclear factor of activated T cells/activator protein 1 transcriptional activity. In vivo prion protein gene-small interfering ribonucleic acid treatment promoted T cell differentiation towards pro-inflammatory phenotypes and increased survival of antigen-specific T cells. Cellular prion protein silencing with small interfering ribonucleic acid also resulted in the worsening of actively induced and adoptively transferred experimental autoimmune encephalomyelitis. Finally, treatment of myelin basic protein1–11 T cell receptor transgenic mice with prion protein gene-small interfering ribonucleic acid resulted in spontaneous experimental autoimmune encephalomyelitis. Thus, central nervous system autoimmune disease was modulated at all stages of disease: the generation of the T cell effector response, the elicitation of T effector function and the perpetuation of cellular immune responses. Our findings indicate that cellular prion protein regulates T cell receptor-mediated T cell activation, differentiation and survival. Defects in autoimmunity are restricted to the immune system and not the central nervous system. Our data identify cellular prion protein as a regulator of cellular immunological homoeostasis and suggest cellular prion protein as a novel potential target for therapeutic immunomodulation.

  D. A Kulkarni , A Vazquez , B. G Haffty , E. V Bandera , W Hu , Y. Y Sun , D. L Toppmeyer , A. J Levine and K. M. Hirshfield
 

Murine double minute 4 (MDM4) shares significant structural homology with murine double minute 2 (MDM2) and interacts and regulates transcriptional activity of the tumor suppressor p53. In tumors with wild-type p53, there is often overexpression of MDM2 or MDM4 leading to functional inactivation of p53. A single-nucleotide polymorphism (SNP) in the promoter of human MDM2 (SNP309) was shown to associate with increased MDM2 expression and increased risk of cancer. This study evaluated the association of a SNP in human MDM4 (C>T) with age of onset of breast cancer in two independent cohorts. In cohort 1 of 675 patients, the average age of diagnosis for women with estrogen receptor (ER)-positive and ER-negative breast cancers was 53.2 and 48 years, respectively. In this cohort, homozygous variant (TT) carriers developed ER-negative carcinomas at an earlier age than homozygous wild-type (CC) or heterozygous (TC) such that the age at diagnosis was accelerated by 5.0 years (P = 0.018). This association was validated in a second cohort of breast cancer patients (n = 148), where TT carriers with ER-negative cancer developed the disease 3.8 years earlier than CC carriers (P = 0.006). The effect was more pronounced in Caucasians with ER-negative ductal carcinomas with TT homozygotes developing disease 7.5 years (P = 0.031) and 6.2 years (P = 7 x 10–5) earlier than CC carriers in cohorts 1 and 2, respectively. No association was seen in ER-positive ductal cancers suggesting that the SNP in MDM4 only has a functional association in ER-negative breast cancer.

  X Li , J He , W Hu and Z. Yin
 

Ghrelin, a multifunctional hormone, including potent GH stimulation activity, has been suggested to be important during embryonic development. Expression of ghrelin has been confirmed in the zebrafish pancreas during embryonic stages. Interfering with ghrelin function using two specific antisense morpholino oligonucleotides causes defects during zebrafish embryonic development. In ghrelin morphants the expression of GH was abolished in zebrafish somatotropes, whereas the expression patterns of the other key molecules involved in hypothalamic-pituitary development and distinct pituitary hormones genes remain largely intact at the appropriate time during zebrafish adenohypophysis development. Effective rescue of the ghrelin morphants with exogenous ghrelin mRNA showed that the correct gene had been targeted. Moreover, by analyzing the efficiencies of the ghrelin morphants rescue experiments with various forms of exogenous mutant ghrelin mRNAs, we also demonstrated the essentiality of the form acyl-ghrelin on GH stimulation during zebrafish adenohypophysis development. Our in vivo experiments, for the first time, also provided evidence of the existence of functional obestatin in the C-terminal part of zebrafish proghrelin peptides. Our research here has demonstrated that zebrafish is a unique model for functional studies of endogenous ghrelin, especially during embryonic development.

  W Hu , F Li , S Mahavadi and K. S. Murthy
 

Initial Ca2+-dependent contraction of intestinal smooth muscle is inhibited upon IL-1β treatment. The decrease in contraction reflects the upregulation of regulator of G protein signaling-4 (RGS4) via the canonical inhibitor of NF-B kinase-2 (IKK2)/IB-/NF-B pathway. Here, we show that the activation of various protein kinases, including ERK1/2, p38 MAPK, and phosphoinositide 3-kinase (PI3K), differentially modulates IL-1β-induced upregulation of RGS4 in rabbit colonic muscle cells. IL-1β treatment caused a transient phosphorylation of ERK1/2 and p38 MAPK. It also caused the phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), sequential downstream effectors of PI3K. Pretreatment with PD-98059 (an ERK inhibitor) and SB-203580 (a p38 MAPK inhibitor) significantly inhibited IL-1β-induced RGS4 expression. In contrast, LY-294002 (a PI3K inhibitor) augmented, whereas GSK3β inhibitors inhibited, IL-1β-induced RGS4 expression. PD-98059 blocked IL-1β-induced phosphorylation of IKK2, degradation of IB-, and phosphorylation and nuclear translocation of NF-B subunit p65, whereas SB-203580 had a marginal effect, implying that the effect of ERK1/2 is exerted on the canonical IKK2/IB-/p65 pathway of NF-B activation but that the effect of p38 MAPK may not predominantly involve NF-B signaling. The increase in RGS4 expression enhanced by LY-294002 was accompanied by an increase in the phosphorylation of IKK2/IB-/p65 and blocked by pretreatment with inhibitors of IKK2 (IKK2-IV) and IB- (MG-132). Inhibition of GSK3β abolished IL-1β-induced phosphorylation of IKK2/p65. These findings suggest that ERK1/2 and p38 MAPK enhance IL-1β-induced upregulation of RGS4; the effect of ERK1/2 reflects its ability to promote IKK2 phosphorylation and increase NF-B activity. GSK3β acts normally to augment the activation of the canonical NF-B signaling. The PI3K/Akt/GSK3β pathway attenuates IL-1β-induced upregulation of RGS4 expression by inhibiting NF-B activation.

 
 
 
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