Neuronal activity-induced BRG1 phosphorylation regulates enhancer activation.

Neuronal activity-induced enhancers drive gene activation. We demonstrate that BRG1, the core subunit of SWI/SNF-like BAF ATP-dependent chromatin remodeling complexes, regulates neuronal activity-induced enhancers. Upon stimulation, BRG1 is recruited to enhancers in an H3K27Ac-dependent manner.

A proteomic approach identifies SAFB-like transcription modulator (SLTM) as a bidirectional regulator of GLI family zinc finger transcription factors.

In Sonic hedgehog (SHH) signaling, GLI family zinc finger (GLI)-mediated diverse gene transcription outcomes are strictly regulated and are important for SHH function in both development and disease. However, how the GLI factors differentially regulate transcription in response to variable SHH activities is incompletely understood. Here, using a newly generated, tagged knock-in mouse ( ), we performed proteomic analyses and identified the chromatin-associated SAFB-like transcription modulator (SLTM) as a GLI-interacting protein that context-dependently regulates GLI activities.

Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling.

Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms.

Chromatin Remodeling Factor Brg1 Supports the Early Maintenance and Late Responsiveness of Nestin-Lineage Adult Neural Stem and Progenitor Cells.

Insights from embryonic development suggest chromatin remodeling is important in adult neural stem cells (aNSCs) maintenance and self-renewal, but this concept has not been fully explored in the adult brain. To assess the role of chromatin remodeling in adult neurogenesis, we inducibly deleted Brg1--the core subunit of SWI/SNF-like Brg1/Brm-associated factor chromatin remodeling complexes--in nestin-expressing aNSCs and their progeny in vivo and in culture. This resulted in abnormal adult neurogenesis in the hippocampus, which initially reduced hippocampal aNSCs and progenitor maintenance, and later reduced its responsiveness to physiological stimulation.

Generation of BAF53b-Cre transgenic mice with pan-neuronal Cre activities.

Molecular and functional studies of genes in neurons in mouse models require neuron-specific Cre lines. The current available neuronal Cre transgenic or knock-in lines either result in expression in a subset of neurons or expression in both neuronal and non-neuronal tissues. Previously we identified BAF53b as a neuron-specific subunit of the chromatin remodeling BAF complexes.

An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth.

The Sonic hedgehog (Shh) signalling pathway plays important roles during development and in cancer. Here we report a Shh-induced epigenetic switch that cooperates with Gli to control transcription outcomes. Before induction, poised Shh target genes are marked by a bivalent chromatin domain containing a repressive histone H3K27me3 mark and an active H3K4me3 mark.

Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development.

Sonic hedgehog (Shh) signaling plays diverse roles during animal development and adult tissue homeostasis through differential regulation of Gli family transcription factors. Dysregulated Shh signaling activities have been linked to birth defects and tumorigenesis. Here we report that Brg, an ATP-dependent chromatin remodeling factor, has dual functions in regulating Shh target gene expression.

Replication-compromised cells require the mitotic checkpoint to prevent tetraploidization.

Replication stress often induces chromosome instability. In this study, we explore which factors in replication-compromised cells promote abnormal chromosome ploidy. We expressed mutant forms of either polymerase α (Polα) or polymerase δ (Polδ) in normal human fibroblasts to compromise DNA replication.

Potent antitumor activity of oncolytic adenovirus expressing mda-7/IL-24 for colorectal cancer.

It has been demonstrated that interleukin 24 (IL-24, also called melanoma differentiation associated gene 7) exerts antitumor activity. In this study, we investigated whether oncolytic adenovirus-mediated gene transfer of IL-24 could induce strong antitumor activity. A tumor-selective replicating adenovirus expressing IL-24 (ZD55-IL-24) was constructed by insertion of an IL-24 expression cassette into the ZD55 vector, which is based on deletion of the adenoviral E1B 55-kDa gene.

Suppression of tumor growth by oncolytic adenovirus-mediated delivery of an antiangiogenic gene, soluble Flt-1.

Armed oncolytic adenoviruses represent an appealing tumor treatment approach, as they can attack tumors at multiple levels. In this study, considering that angiogenesis plays a central role in tumor growth, we inserted an antiangiogenic gene, sflt-1(1-3) (the first three extracellular domains of FLT1, the hVEGF receptor-1), into an E1B-55-kDa-deleted oncolytic adenovirus (ZD55) to construct ZD55-sflt-1. Although soluble (s) Flt-1 did not affect tumor cell growth, ZD55-sflt-1 could specifically induce a cytopathic effect in tumor cells, like ONYX-015.

Suppression of morphine withdrawal syndrome by interleukin-2 and its gene.

The naloxone-precipitated withdrawal syndrome in mice and rats after intrathecal injection of recombinant human interleukin-2 protein (rIL-2) or its gene was studied. The results showed that rIL-2 could significantly decrease the number of jumps in mice. In rats, rIL-2 significantly suppressed irritating, diarrhea, weight loss, abnormal posture and salivation.

HSF1 blockade-induced tumor thermotolerance abolishment is mediated by JNK-dependent caspase-3 activation.

We previously blocked the heat shock transcription factor 1 function with a dominant-negative mutant (mHSF1) in breast cancer cell line Bcap37, and found that mHSF1 sensitizes Bcap37 cells to hyperthermia by promoting the apoptotic process. Here we studied the mechanism of this abolishing process and how thermotolerance develops in Bcap37 cells. The results indicated that mHSF1 abolished acquired or intrinsic thermotolerance in Bcap37 cells by enhancing JNK and caspase-3 pathways, two stress-induced apoptotic pathways, after hyperthermia, and interference with either one of them attenuated hyperthermia-induced apoptosis.

Combination of Targeting Gene-ViroTherapy with 5-FU enhances antitumor efficacy in malignant colorectal carcinoma.

To improve the therapeutic effect of ONYX015, an E1B55kD-deleted replication-competent adenovirus, ZD55 was constructed and armed with the therapeutic gene hTRAIL to form ZD55-hTRAIL, which was used for cancer therapy and which we call Targeting Gene-ViroTherapy. In vitro experiments with SW620, HCT116, and HT29 colorectal carcinoma cell lines demonstrated that they were all sensitive to ZD55-hTRAIL, and especially sensitive to ZD55-hTRAIL plus 5-fluorouracil (5-FU) treatment. In the SW620 xenograft tumor model, various treatment groups showed marked differences at week 11, with the tumor volume for the phosphate-buffered saline (PBS) treatment group >1700 mm3, for 5-FU > 1300 mm3, for ONYX015 1051.

An oncolytic adenoviral vector of Smac increases antitumor activity of TRAIL against HCC in human cells and in mice.

Hepatocellular carcinoma (HCC) displays a high resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cell death. To increase sensitivity of HCC cells to TRAIL, we have constructed an oncolytic adenoviral vector (ZD55) and used this vector to deliver second mitochondria-derived activator of caspases (Smac) and TRAIL genes (ZD55-Smac and ZD55-TRAIL, respectively) into HCC cells. Our data showed that human HCC cells express high levels of inhibitor of apoptosis proteins (IAPs).

A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent.

Telomerase is a therapeutic target for cancer. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase, is transcriptionaly upregulated exclusively in about 90% of cancer cells. Previous studies have demonstrated that hTERT promoter can control the expression of exogenous genes to the telomerase-positive cancer cells, thus hTERT promoter is an excellent candidate for generating cancer-specific oncolytic adenovirus.

Current strategies and future directions of antiangiogenic tumor therapy.

Neovascularization is a prerequisite for progressive growth of most tumors and their metastases. Therefore, inhibition of angiogenesis could be one of the most promising strategies that might lead to the development of novel anticancer therapy. New blood vessels forming in tumors can be avoided by interfering the process of angiogenesis through suppressing the proangiogenic signal or augmenting the antiangiogenic factors.