Biomedical subjects

Zhengqi Wang

Publications and source records attributed to Zhengqi Wang.

5 recordsLinked to original sources

PubMed2006

Stat5 expression is required for IgE-mediated mast cell function.

The mast cell (MC) inflammatory response is now linked not only to atopy, but also to arthritis, multiple sclerosis, heart disease, and resistance to bacterial infection. In the current study, we demonstrate that the signal transducer and activator of transcription 5 (Stat5) is rapidly activated by IgE cross-linkage, and that its expression is critical to the MC response. Stat5-deficient (Stat5KO) MC demonstrated a significant decrease in IgE-mediated degranulation, leukotriene B4 production, cytokine secretion, and survival signals. The defect in cytokine production may be caused by decreased cytokine mRNA stability. Stat5KO MC-induced cytokine mRNAs normally following IgE cross-linkage, but these mRNAs were not sustained over time and were degraded at twice the rate observed in WT cells. Interestingly, the RNA destabilizing protein tristetraprolin was induced following IgE cross-linkage in Stat5KO but not wild-type cells. Moreover, reducing tristetraprolin expression via short hairpin RNA transfection significantly increased IL-13 production in Stat5KO MC. Our work demonstrates that Stat5 is a critical factor in IgE-induced MC activation, acting in part via posttranscriptional control of cytokine mRNA stability. These data have a direct impact on MC-associated inflammatory and autoimmune diseases.

Animals↗

PubMed2004

The glucocorticoid-induced gene tdag8 encodes a pro-apoptotic G protein-coupled receptor whose activation promotes glucocorticoid-induced apoptosis.

The apoptotic action of glucocorticoids on lymphocytes makes them effective therapeutics for many lymphoid malignancies. Although it is clear that glucocorticoid-induced apoptosis requires transcription, the gene products that induce apoptosis remain unknown. Using gene expression profiles of lymphoma cell lines and primary thymocytes treated with the synthetic glucocorticoid dexamethasone, we discovered that induction of tdag8 (T-cell death-associated gene 8) was a common event in each model system investigated. Activation of TDAG8 by its agonist psychosine markedly enhanced dexamethasone-induced apoptosis in a TDAG8-dependent manner. Expression of a TDAG8-GFP fusion protein was sufficient to induce apoptosis, and repression of endogenous TDAG8 using RNA interference partially inhibited dexamethasone-induced apoptosis. Together, these data suggest that TDAG8 is a regulator of glucocorticoid-induced apoptosis and that agonists of TDAG8 may be promising agents to improve the efficacy of glucocorticoids for the treatment of leukemia and lymphoma.

Algorithms↗

PubMed2003

Dexamethasone-induced gene 2 (dig2) is a novel pro-survival stress gene induced rapidly by diverse apoptotic signals.

Glucocorticoid hormones induce apoptosis in lymphoid cells. This process requires de novo RNA/protein synthesis. Here we report the identification and cloning of a novel dexamethasone-induced gene designated dig2. Using Affymetrix oligonucleotide microarray analysis of approximately 10,000 genes and expressed sequence tags, we found that the expression of dig2 mRNA is significantly induced not only in the murine T cell lymphoma lines S49.A2 and WEHI7.2 but also in normal mouse thymocytes following dexamethasone treatment. This result was confirmed by Northern blot analysis. The induction of dig2 mRNA by dexamethasone appears to be mediated through the glucocorticoid receptor as it is blocked in the presence of RU486, a glucocorticoid receptor antagonist. Furthermore, we demonstrated that dig2 is a novel stress response gene, as its mRNA is induced in response to a variety of cellular stressors including thapsigargin, tunicamycin, and heat shock. In addition, the levels of dig2 mRNA were up-regulated after treatment with the apoptosis-inducing chemotherapeutic drug etoposide. Though the function of dig2 is unknown, dig2 appears to have a pro-survival function, as overexpression of dig2 reduces the sensitivity of WEHI7.2 cells to dexamethasone-induced apoptosis.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis.

Despite being one of the earliest recognized and most clinically relevant forms of apoptosis, little is known about the transcriptional events that mediate glucocorticoid-induced apoptosis. Therefore, we used oligonucleotide microarrays to identify the pattern of dexamethasone-induced changes in gene expression in two well characterized models of glucocorticoid-induced apoptosis, the murine lymphoma cell lines S49.A2 and WEHI7.2. Dexamethasone treatment induced a diverse set of gene changes that evolved over a 24-h period preceding the onset of cell death. These include previously reported changes in the expression of genes regulating prosurvival signals mediated by c-Myc and NFkappaB. Unexpectedly, we discovered that glucocorticoid treatment increases expression of the gene encoding Bim, a BH3-only member of the Bcl-2 family that is capable of directly activating the apoptotic cascade. Induction of Bim was confirmed by immunoblotting not only in S49.A2 and WEHI7.2 cells but also in the human leukemia cell line CEM-C7 and in primary murine thymocytes. All three prototypical isoforms of Bim (BimEL, BimL, and BimS) were induced by dexamethasone. Because elevated expression of Bim initiates the execution phase of cell death, this report that Bim is induced by dexamethasone provides novel insight into the mechanism through which glucocorticoid-mediated changes in gene expression induce apoptosis in lymphoid cells.

Animals↗

PubMed2002

Bcl-2 on the endoplasmic reticulum regulates Bax activity by binding to BH3-only proteins.

Bcl-2 family members have been shown to be key mediators of apoptosis as either pro- or anti-apoptotic factors. It is thought that both classes of Bcl-2 family members act at the level of the mitochondria to regulate apoptosis, although the founding anti-apoptotic family member, Bcl-2 is localized to the endoplasmic reticulum (ER), mitochondrial, and nuclear membranes. In order to better understand the effect of Bcl-2 localization on its activity, we have utilized a Bcl-2 mutant that localizes only to the ER membrane, designated Bcl-2Cb5. Bcl-2Cb5 was expressed in MDA-MB-468 cells, which protected against apoptosis induced by the kinase inhibitor, staurosporine. Data presented here show that Bcl-2Cb5 inhibits this process by blocking Bax activation and cytochrome c release. Furthermore, we show that Bcl-2Cb5 can inhibit the activation of a constitutively mitochondrial mutant of Bax, indicating that an intermediate between Bcl-2 on the ER and Bax on the mitochondria must exist. We demonstrate that this intermediate is likely a BH3-only subfamily member. Data presented here show that Bcl-2Cb5 can sequester a constitutively active form of Bad (Bad3A) from the mitochondria and prevent it from activating Bax. These data suggest that Bcl-2 indirectly protects mitochondrial membranes from Bax, via BH3-only proteins.

Apoptosis↗