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author:("Li, weiguan")
1.  ATF4 activity: a common feature shared by many kinds of slow-aging mice 
Aging Cell  2014;13(6):1012-1018.
ATF4, a DNA-binding factor that modulates responses to amino acid availability and ribosomal function, has been shown to be altered in both liver and fibroblasts from two strains of long-lived mice, i.e. Snell dwarf and PAPP-A knockout mice. New data now show elevated ATF4 levels, and elevation of ATF4-dependent proteins and mRNAs, in liver of mice treated with acarbose or rapamycin, calorically restricted mice, methionine-restricted mice, and mice subjected to litter crowding. Elevation of ATF4, at least in liver, thus seems to be a shared feature of diets, drugs, genes, and developmental alterations that extend maximum lifespan in mice.
PMCID: PMC4326926  PMID: 25156122
acarbose; caloric restriction; longevity; methionine restriction; rapamycin
2.  Expression of multidrug resistance proteins in invasive ductal carcinoma of the breast 
Oncology Letters  2014;8(5):2103-2109.
Chemotherapy is commonly used for the treatment of breast cancer. However, the resistance to chemotherapeutic agents, often mediated by multidrug resistance (MDR) mechanisms, is a common occurrence. The present study examined the expression of several MDR-related proteins (MRPs) in invasive ductal carcinoma (IDC) of the breast, and assessed their association with clinicopathological variables and their prognostic significance. In addition, immunohistochemistry was used to measure the expression of MRP, p-glycoprotein (P-gp), topoisomerase 2α (Topo2α), thymidylate synthase (TS) and glutathione-S-transferase π (GST-π) in 156 resected IDCs of the breast. Pearson’s χ2 test and Spearman’s correlation coefficient were used to analyze the association between MDR protein expression and several clinicopathological variables. The association between each of the five MDR proteins was also examined. Furthermore, Kaplan-Meier analysis and Cox regression modeling were used to assess overall survival. The expression of MRP, P-gp, Topo2α, TS and GST-π was detected in 20.5% (32/156), 25.0% (39/156), 84.0% (131/156), 41.7% (65/156) and 41.0% (64/156) of cases examined, respectively. No correlation was identified between MRP and Topo-2α and the clinicopathological variables examined. By contrast, P-gp (χ2=20.226; P<0.0001) and GST-π (χ2=35.032; P<0.0001) were found to positively correlate with tumor grade. In addition, staining for TS was associated with axillary lymph node metastasis (χ2=42.281; P<0.0001). The expression levels of P-gp and GST-π were found to be significantly correlated (r= 0.319; P<0.0001). Furthermore, GST-π expression was elevated in estrogen receptor-negative breast cancer (χ2=17.407; P<0.0001). Tumor histological grade, in addition to TS and GST-π expression, were significant predictors of a poor survival outcome. TS and GST-π are consequently useful prognostic biomarkers in IDC, therefore, when establishing a personalized chemotherapeutic plan, the expression of MDR proteins must be considered.
PMCID: PMC4186596  PMID: 25295098
breast neoplasm; multidrug resistance-related protein; topoisomerase2α; thymidylate synthase; glutathione-s-transferase π; multidrug resistance; immunohistochemistry; p-glycoprotein
3.  FOXP3 Regulates Sensitivity of Cancer Cells to Irradiation by Transcriptional Repression of BRCA1 
Cancer research  2013;73(7):10.1158/0008-5472.CAN-12-2481.
FOXP3 is an X-linked tumor suppressor gene and a master regulator in T regulatory cell function. This gene has been found to be mutated frequently in breast and prostate cancers and to inhibit tumor cell growth, but its functional significance in DNA repair has not been studied. We found that FOXP3 silencing stimulates homologous recombination-mediated DNA repair and also repair of γ-irradiation-induced DNA damage. Expression profiling and chromatin-immunoprecipitation analyses revealed that FOXP3 regulated the BRCA1-mediated DNA repair program. Among 48 FOXP3-regulated DNA repair genes, BRCA1 and 12 others were direct targets of FOXP3 transcriptional control. Site-specific interaction of FOXP3 with the BRCA1 promoter repressed its transcription. Somatic FOXP3 mutants identified in breast cancer samples had reduced BRCA1 repressor activity, while FOXP3 silencing and knock-in of a prostate cancer-derived somatic FOXP3 mutant increased the radioresistance of cancer cells. Together our findings provide a missing link between FOXP3 function and DNA repair programs.
PMCID: PMC3815443  PMID: 23319807
4.  FOXP3 Orchestrates H4K16 Acetylation and H3K4 Tri-Methylation for Activation of Multiple Genes through Recruiting MOF and Causing Displacement of PLU-1 
Molecular cell  2011;44(5):770-784.
Both H4K16 acetylation and H3K4 tri-methylation are required for gene activation. However, it is still largely unclear how these modifications are orchestrated by transcriptional factors. Here we analyzed the mechanism of the transcriptional activation by FOXP3, an X-linked suppressor of autoimmune diseases and cancers. FOXP3 binds near transcriptional start sites of its target genes. By recruiting MOF and displacing histone H3K4 demethylase PLU-1, FOXP3 increases both H4K16 acetylation and H3K4 tri-methylation at the FOXP3-associated chromatins of multiple FOXP3-activated genes. RNAi-mediated silencing of MOF reduced both gene activation and tumor suppression by FOXP3, while both somatic mutations in clinical cancer samples and targeted mutation of FOXP3 in mouse prostate epithelial disrupted nuclear localization of MOF. Our data demonstrate a pull-push model in which a single transcription factor orchestrates two epigenetic alterations necessary for gene activation and provide a mechanism for somatic inactivation of the FOXP3 protein function in cancer cells.
PMCID: PMC3243051  PMID: 22152480
5.  Identification of a Tumor Suppressor Relay between the FOXP3 and the Hippo Pathways in Breast and Prostate Cancers 
Cancer research  2011;71(6):2162-2171.
Defective expression of LATS2, a negative regulator of YAP onco-protein, has been reported in cancer of prostate, breast, liver, brain and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in prostate, breast, liver, brain and blood cancers. However, the basis for LATS2 dysregulation in cancer is undefined. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer.
PMCID: PMC3070402  PMID: 21278236
prostate cancer; breast cancer; Hippo pathway; FoxP3; tumor suppressor genes
6.  Somatic Single-hits Inactivate the X-linked Tumor Suppressor FOXP3 in the Prostate 
Cancer cell  2009;16(4):336-346.
Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly over-expressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Since the male has only one X chromosome, our data represents a paradigm of “single-genetic-hit” inactivation-mediated carcinogenesis.
PMCID: PMC2758294  PMID: 19800578
7.  ATF2 and c-Jun-Mediated Induction of FoxP3 for Experimental Therapy of Mammary Tumor in the Mouse 
Cancer research  2009;69(14):5954-5960.
FOXP3 is inactivated in breast cancer cells by a number of mechanisms, including somatic mutations, deletion and epigenetic silencing. Since the mutation and deletion are usually heterozygous in the cancer samples, it is of interest to determine whether the gene can be induced for the purpose of cancer therapy. Here we report that anisomycin, a potent activator of ATF2, and JNK, induces expression of FoxP3 in both normal and malignant mammary epithelial cells. The induction is mediated by ATF2 and c-Jun. Targeted mutation of ATF2 abrogates both constitutive and inducible expression of FoxP3 in normal epithelial cells. Both ATF2 and c-Jun interact with a novel enhancer in the intron 1 of the FoxP3 locus. Moreover, shRNA silencing of ATF2 and FoxP3 reveals an important role of ATF2-FoxP3 pathway in the anisomycin-induced apoptosis of breast cancer cells. A low dose of anisomycin was also remarkably effective in treating established mammary tumor in the mice. Our data demonstrated that FoxP3 can be reactivated for cancer therapy.
PMCID: PMC2742913  PMID: 19584270
FoxP3; breast cancer; tumor suppressor gene
8.  FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene 
Cell  2007;129(7):1275-1286.
The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germ-line mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that Foxp3sf/+ heterozygous mice developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and ErbB2 was over-expressed. Foxp3 bound and repressed the ErbB2 promoter. Deletion, functionally significant somatic mutations and down-regulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2 over-expression, regardless of the status of HER-2 amplification. In toto, the data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.
PMCID: PMC1974845  PMID: 17570480
9.  Activation of FAK and Src are receptor-proximal events required for netrin signaling 
Nature neuroscience  2004;7(11):1213-1221.
The axon guidance cue netrin is importantly involved in neuronal development. DCC (deleted in colorectal cancer) is a functional receptor for netrin and mediates axon outgrowth and the steering response. Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.
PMCID: PMC2373267  PMID: 15494734
10.  FAK and Src kinases are required for netrin-induced tyrosine phosphorylation of UNC5 
Journal of cell science  2006;119(Pt 1):47-55.
During neuronal development, netrin and its receptors UNC5 and DCC (deleted in colorectal cancer) guide axonal growth cones in navigating to their targets. Netrin also plays important roles in the regulation of cell migration, tissue morphogenesis and tumor growth. Here, we show that netrin induces UNC5 tyrosine phosphorylation and that this effect of netrin is dependent on its co-receptor DCC. UNC5 tyrosine phosphorylation is known to be important for netrin to induce cell migration and axonal repulsion. Src tyrosine kinase activity is required for netrin to stimulate UNC5 tyrosine phosphorylation in neurons and transfected cells. The SH2 domain of Src kinase directly interacts with the cytosolic domain of UNC5 in a tyrosine-phosphorylation-dependent manner. Furthermore, the tyrosine kinase focal adhesion kinase (FAK) is also involved in netrin-induced UNC5 tyrosine phosphorylation. Both Src and FAK can phosphorylate UNC5. Our data suggest a model in which netrin stimulates UNC5 tyrosine phosphorylation and signaling in a manner dependent on the co-receptor DCC, through the recruitment of Src and FAK kinases.
PMCID: PMC2248276  PMID: 16371650
Src family tyrosine kinases; Focal adhesion kinase; FAK; Deleted in colorectal cancer; DCC; UNC5 receptor; Netrin signaling; Tyrosine phosphorylation
11.  p130CAS Is Required for Netrin Signaling and Commissural Axon Guidance 
Netrins are an important family of axon guidance cues. Here, we report that netrin-1 induces tyrosine phosphorylation of p130CAS (Crk-associated substrate). Our biochemical studies indicate that p130CAS is downstream of the Src family kinases and upstream of the small GTPase Rac1 and Cdc42. Inhibition of p130CAS signaling blocks both the neurite outgrowth-promoting activity and the axon attraction activity of netrin-1. p130CAS RNA interference inhibits the attraction of commissural axons in the spinal cord by netrin-1 and causes defects in commissural axon projection in the embryo. These results demonstrate that p130CAS is a key component in the netrin signal transduction pathway and plays an important role in guiding commissural axons in vivo.
PMCID: PMC2014516  PMID: 17251438
netrin-1; p130CAS; Rac1; Cdc42; signaling; commissural axons
12.  SRC-1 Mediates UNC-5 Signaling in Caenorhabditis elegans 
Molecular and Cellular Biology  2005;25(15):6485-6495.
The secreted molecule unc-6/netrin is important for guiding axon projections and cell migrations. unc-5 and unc-40/DCC are identified as receptors for unc-6/netrin. The downstream factors of unc-6 receptors are beginning to be elucidated, and some key factors have been identified in various organisms. Here, we showed that SRC-1 interacts with the cytosolic domain of UNC-5 through its SH2 domain. This interaction also requires the intact kinase activity of SRC-1. Downregulation of src-1 by RNA interference decreases the biological processes initiated by the UNC-5 protein and decreases UNC-5 tyrosine phosphorylation. We also generated a chimeric protein consisting of the extracellular domain and transmembrane domain of UNC-5 and an intracellular domain of SRC-1. This fusion protein is able to partially rescue mutant phenotypes caused by unc-5 but not unc-6, unc-40, and unc-34. Our results support a model in which SRC-1 is required for UNC-5-induced axon repulsion and gonad migration signaling pathways and in which localizing SRC-1 activity to UNC-5 is crucial for proper signal transduction in response to unc-6/netrin.
PMCID: PMC1190325  PMID: 16024786

Results 1-12 (12)