Biomedical subjects

Qianben Wang

Publications and source records attributed to Qianben Wang.

8 recordsLinked to original sources

PubMed2025

Single-dose cathepsin L CRISPR nanotherapy mitigates PASC-like lung damage in hamsters.

Respiratory post-acute sequelae of COVID-19 (PASC) persists in many SARS-CoV-2 survivors, yet no therapies specifically address its long-term pulmonary damage. We demonstrate that a single-dose CRISPR-CasRx nanotherapy targeting the host enzyme cathepsin L (SCNC) effectively reduces acute SARS-CoV-2 infection in Syrian hamsters, with antiviral efficacy comparable to Paxlovid. Importantly, SCNC outperforms Paxlovid in alleviating alveolar epithelial hyperplasia and lung inflammation at 31 days post-infection, a recognized PASC time point. Single-cell RNA sequencing reveals that SCNC enhances alveolar repair by promoting the differentiation of alveolar type 2 cells into alveolar type 1 cells and by reducing inflammatory infiltration through multiple signaling pathways. Thus, SCNC exerts a dual mechanism: host-directed viral inhibition and promotion of epithelial repair with reduced inflammation. This distinguishes it from therapies focused solely on viral suppression or symptom relief. These findings support SCNC as a promising therapeutic candidate for acute infection and, particularly, for PASC-related lung injury, where options remain limited.

alveolar epithelial regeneration↗

PubMed2006

Genome-wide analysis of estrogen receptor binding sites.

The estrogen receptor is the master transcriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target. We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale, identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this unique resource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediated gene regulation, particularly in the case of estrogen-suppressed genes. Furthermore, this resource has allowed the identification of cis-regulatory sites in previously unexplored regions of the genome and the cooperating transcription factors underlying estrogen signaling in breast cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Primate-specific evolution of an LDLR enhancer.

BACKGROUND: Sequence changes in regulatory regions have often been invoked to explain phenotypic divergence among species, but molecular examples of this have been difficult to obtain. RESULTS: In this study we identified an anthropoid primate-specific sequence element that contributed to the regulatory evolution of the low-density lipoprotein receptor. Using a combination of close and distant species genomic sequence comparisons coupled with in vivo and in vitro studies, we found that a functional cholesterol-sensing sequence motif arose and was fixed within a pre-existing enhancer in the common ancestor of anthropoid primates. CONCLUSION: Our study demonstrates one molecular mechanism by which ancestral mammalian regulatory elements can evolve to perform new functions in the primate lineage leading to human.

Amino Acid Motifs↗

PubMed2005

Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking.

Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer, where it is a key therapeutic target. Here we report that, in contrast to estrogen receptor transcription complexes which form within minutes and recycle hourly, the levels of regulatory regions bound by AR complexes rise over a 16 hr period and then slowly decline. AR regulation of the prostate specific antigen (PSA) gene involves both a promoter-proximal sequence as well as an enhancer approximately 4 kb upstream. Recruitment of AR and its essential coactivators at both sites creates a chromosomal loop that allows RNA polymerase II (pol II) to track from the enhancer to the promoter. Phosphorylation of the pol II C-terminal domain is required for pol II tracking but not chromosomal looping. Development of improved hormonal therapies for prostate cancer must take in account the specific spatial and temporal modes of AR-mediated gene regulation.

Androgens↗

PubMed2004

Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells.

Androgen receptor (AR) signaling pathways mediate critical events in normal and neoplastic prostate growth. Shortening of the polymorphic N-terminal polyglutamine (poly(Q)) tract of the AR gene leads to transcriptional hyperactivity and has been correlated with an increased risk of prostate cancer. The underlying mechanisms for these effects are poorly understood. We show here that androgen-dependent cellular proliferation and transcription in prostate cancer cells is inversely correlated to the length of the AR poly(Q) region. We further show that AR proteins containing a shortened poly(Q) region functionally respond to lower concentrations of androgens than wild type AR. Whereas DNA binding activity is relatively unaffected by AR poly(Q) variation, we found that ligand binding affinity and the ligand-induced NH(2)- to COOH-terminal intramolecular interaction is enhanced when the poly(Q) region is shortened. Importantly, we show that AR proteins containing a shortened poly(Q) region associate in vivo with higher levels of specific p160 coactivators and components of the SWI/SNF chromatin remodeling complex as compared with the wild type AR. Collectively, our findings suggest that the AR transcriptional hyperactivity associated with shortened poly(Q) length stems from altered ligand-induced conformational changes that enhance coactivator recruitment.

Blotting, Western↗

PubMed2002

A coregulatory role for the TRAP-mediator complex in androgen receptor-mediated gene expression.

The human thyroid hormone receptor-associated protein (TRAP)-Mediator complex was originally identified as a large multimeric complex that copurifies with the thyroid hormone receptor (TR) from HeLa cells and markedly enhances TR-mediated transcription in vitro. More recent studies have implicated TRAP-Mediator as a coactivator for a broad range of nuclear hormone receptors as well as other classes of transcriptional activators. Here we present evidence that TRAP-Mediator plays a functional role in androgen receptor (AR)-mediated transcription. We show that several subunits of the complex ligand-dependently coimmunoprecipitate with AR from both prostate cancer LNCaP cells and from HeLa cells stably transfected with AR. The 220-kDa subunit of the complex (TRAP220) can contact the ligand-binding domain of AR in vitro, possibly implicating TRAP220 involvement in targeting AR to the holocomplex. Consistent with a TRAP-Mediator coactivator role, transient overexpression of the TRAP220, TRAP170, and TRAP100 subunits enhanced ligand-dependent transcription by AR in cultured cells. Finally, chromatin immunoprecipitation assays show that TRAP220 is recruited to the androgen-responsive prostate-specific antigen gene promoter in vivo in ligand-stimulated LNCaP cells. Collectively, these data suggest that TRAP-Mediator may play an important coregulatory role in AR-mediated gene expression.

Antigens, Neoplasm↗

PubMed2002

Repression of androgen receptor mediated transcription by the ErbB-3 binding protein, Ebp1.

Members of the ErbB family of receptors have been implicated in regulation of androgen receptor (AR) activity. Ebp1, an ErbB-3 binding protein recently cloned in our laboratory, possesses an LXXLL motif important in mediating interactions with nuclear hormone receptors. Therefore, we sought to determine if Ebp1 could bind AR and influence AR transcriptional activation potential. We demonstrate in this study that Ebp1 bound to AR in vitro and in vivo, and that this binding was increased by androgen treatment. The C terminal 79 amino acids of Ebp1 were sufficient to bind AR. The N terminal domain of AR was responsible for binding Ebp1. Ligand-mediated transcriptional activation of both artificial and natural AR regulated promoters was inhibited by ectopic expression of ebp1 in transient transfection systems. Ebp1 deletion mutants that either lacked the C terminal AR binding region or had a mutated LXXLL motif failed to inhibit AR activated transcription. PSA expression from its endogenous promoter was also decreased in LNCaP prostate cancer cells overexpressing Ebp1. The growth of AR positive LNCaP cells was inhibited by ectopic expression of ebp1, but mutants that failed to repress transcription did not inhibit cell growth. These studies suggest that Ebp1 may play a role in the function of the AR and provide a link between ErbB receptors and the AR.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Effects of total glycosides from Baishouwu on human breast and prostate cancer cell proliferation.

Baishouwu (Cynanchum Auriculalum Royle ex Wight), a traditional Chinese herbal medicine, is used as a traditional anti-aging remedy in China. Previous studies suggested Baishouwu has multiple pharmacological actions. In this study, the total glycosides extracted from Baishouwu (CA/TG) were evaluated for its potential anti-tumor activity and mechanism on several human breast and prostate cancer cell lines. In [3H] thymidine incorporation assay. CA/TG inhibited the proliferation of cancer cells in a dose-dependent fashion. It also displayed anti-androgen activity on androgen sensitive cell line assessed by reporter gene assay. The morphological examination of CA/TG treated cells revealed overall shrinkage of nucleus, chromatin condensation and small nuclear fragments by DAPI staining, the characteristic pattern of DNA ladders were observed in cells exposed to CA/TG, indicating the involvement of apoptosis in its action. These results suggested that the CA/TG has preferred cytotoxicity against the cancer cells, and the action was due to its ability of preventing cell proliferation and inducing apoptosis.

Antineoplastic Agents, Phytogenic↗