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Xiaosheng Wu

Publications and source records attributed to Xiaosheng Wu.

7 recordsLinked to original sources
PubMed2006

A role for BLyS in the activation of innate immune cells.

B-lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor (TNF) ligand superfamily. Although BLyS costimulates adaptive immune cells, the ability of BLyS to stimulate innate immune cells has not been described. Here, we show that BLyS strongly induces human monocyte survival, and activation as measured by proinflammatory cytokine secretion and up-regulation of costimulatory molecule expression. In addition, monocytes cultured with BLyS differentiated into macrophage-like cells. Regarding BLyS receptor(s) expression, freshly isolated monocytes bound low levels of exogenous BLyS and expressed primarily intracellular TACI, and cell surface TACI levels increased following monocyte activation. Of interest, bone marrow monocytes from some multiple myeloma patients expressed significant levels of cell surface TACI at isolation. Our findings indicate that BLyS plays a role in activating innate immune cells. Moreover, this study may explain more clearly why high BLyS production is often correlated with certain inflammatory autoimmune diseases and B-lymphocyte malignancies.

Apoptosis↗
PubMed2005

The double-edged sword of activation-induced cytidine deaminase.

Activation-induced cytidine deaminase (AID) is required for Ig class switch recombination, a process that introduces DNA double-strand breaks in B cells. We show in this study that AID associates with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promoting cell survival, presumably by resolving DNA double-strand breaks. Wild-type cells expressing AID mutants that fail to associate with DNA-PKcs or cells deficient in DNA-PKcs or 53BP1 expressing wild-type AID accumulate gammaH2AX foci, indicative of heightened DNA damage response. Thus, AID has two independent functions. AID catalyzes cytidine deamination that originates DNA double-strand breaks needed for recombination, and it promotes DNA damage response and cell survival. Our results thus resolve the paradox of how B cells undergoing DNA cytidine deamination and recombination exhibit heightened survival and suggest a mechanism for hyperIgM type II syndrome associated with AID mutants deficient in DNA-PKcs binding.

Animals↗
PubMed2005

Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines.

OBJECTIVE: To measure mRNA expression levels of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines and to determine if DNA methylation is involved in the control of PEG3 expression. METHODS: PEG3 mRNA levels were measured with real-time PCR from 28 gynecologic cancer cell lines and compared to normal tissues. PEG3 mRNA expression was correlated to promoter methylation levels measured by real-time methylation-specific PCR. Polymorphism-specific restriction digestion was employed to analyze PEG3 allele distribution. RESULTS: While expressed in normal gynecologic tissues, PEG3 is silenced in all endometrial and cervical cancer cell lines studied. In the eight ovarian cancer cell lines, five were found to be PEG3 negative, the remaining three express low levels of PEG3 mRNA. In contrast, loss of maternal imprinting and relatively high PEG3 expression levels were detected in all four choriocarcinomas cell lines studied. No cell line confirmed to contain two copies of PEG3 expressed PEG3 mRNA, suggesting that PEG3 downregulation is not due to genetic deletion. PEG3 mRNA expression was, however, quantitatively correlated to its promoter methylation status. Treatment of PEG3 negative cells with DNA methyltransferase inhibitor 5'-aza-deoxycytidine led to partial promoter demethylation and biallelic reactivation of PEG3 transcription, confirming the methylation-mediated mechanism for PEG3 silencing. CONCLUSION: PEG3 silencing is associated with DNA hypermethylation but not gene deletion in cell lines tested. These results suggest that loss of PEG3 expression may be a frequent event in gynecologic cancers. Given the known role of PEG3 in p53-mediated apoptosis, it is possible that PEG3 functions as a tumor suppressor.

Alleles↗
PubMed2005

A-Miz-ing BCL6.

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Animals↗
PubMed2003

Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation.

The WD-repeat proteins Rae1 and Bub3 show extensive sequence homology, indicative of functional similarity. However, previous studies have suggested that Rae1 is involved in the mRNA export pathway and Bub3 in the mitotic checkpoint. To determine the in vivo roles of Rae1 and Bub3 in mammals, we generated knockout mice that have these genes deleted individually or in combination. Here we show that haplo-insufficiency of either Rae1 or Bub3 results in a similar phenotype involving mitotic checkpoint defects and chromosome missegregation. We also show that overexpression of Rae1 can correct for Rae1 haplo-insufficiency and, surprisingly, Bub3 haplo-insufficiency. Rae1-null and Bub3-null mice are embryonic lethal, although cells from these mice did not have a detectable defect in nuclear export of mRNA. Unlike null mice, compound haplo-insufficient Rae1/Bub3 mice are viable. However, cells from these mice exhibit much greater rates of premature sister chromatid separation and chromosome missegregation than single haplo-insufficient cells. Finally, we show that mice with mitotic checkpoint defects are more susceptible to dimethylbenzanthrene-induced tumorigenesis than wild-type mice. Thus, our data demonstrate a novel function for Rae1 and characterize Rae1 and Bub3 as related proteins with essential, overlapping, and cooperating roles in the mitotic checkpoint.

Active Transport, Cell Nucleus↗
PubMed2003

Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.

DNA mismatch repair maintains genomic stability by detecting and correcting mispaired DNA sequences and by signaling cell death when DNA repair fails. The mechanism by which mismatch repair coordinates DNA damage and repair with cell survival or death is not understood, but it suggests the need for regulation. Since the functions of mismatch repair are initiated in the nucleus, we asked whether nuclear transport of MLH1 and PMS2 is limiting for the nuclear localization of MutLalpha (the MLH1-PMS2 dimer). We found that MLH1 and PMS2 have functional nuclear localization signals (NLS) and nuclear export sequences, yet nuclear import depended on their C-terminal dimerization to form MutLalpha. Our studies are consistent with the idea that dimerization of MLH1 and PMS2 regulates nuclear import by unmasking the NLS. Limited nuclear localization of MutLalpha may thus represent a novel mechanism by which cells fine-tune mismatch repair functions. This mechanism may have implications in the pathogenesis of hereditary non-polyposis colon cancer.

Active Transport, Cell Nucleus↗