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Zfra affects TNF-mediated cell death by interacting with death domain protein TRADD and negatively regulates the activation of NF-κB, JNK1, p53 and WOX1 during stress response
Qunying Hong, Li-Jin Hsu, Lori Schultz, Nicole Pratt, Jeffrey Mattison, Nan-Shan Chang
BMC Molecular Biology , 2007, DOI: 10.1186/1471-2199-8-50
Abstract: Transiently overexpressed Zfra caused growth suppression and apoptotic death of many but not all types of cells. Zfra either enhanced or blocked cell death caused by TRADD, FADD, or receptor-interacting protein (RIP) in a dose-related manner. This modulation is related with Zfra binding with TRADD, NF-κB, JNK1 and WOX1, as determined by GST pull-down analysis, co-immunoprecipitation, and mapping by yeast two-hybrid analysis. Functionally, transiently overexpressed Zfra sequestered NF-κB (p65), WOX1, p53 and phospho-ERK (extracellular signal-activated kinase) in the cytoplasm, and TNF or UV light could not effectively induce nuclear translocation of these proteins. Zfra counteracted the apoptotic functions of Tyr33-phosphorylated WOX1 and Ser46-phosphorylated p53. Alteration of Ser8 to Gly abolished the apoptotic function of Zfra and its regulation of WOX1 and p53.In response to TNF, Zfra is upregulated and modulates TNF-mediated cell death via interacting with TRADD, FADD and RIP (death-inducing signaling complex) at the receptor level, and downstream effectors NF-κB, p53, WOX1, and JNK1.Human WWOX/FRA16D gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase, designated WWOX, FOR, or WOX1 [1-3]. This gene is located on a common fragile site ch16q23.3–24.1 [1,2]. Loss of heterozygosity (LOH) of WWOX gene has been found in several types of cancers [[4,5]; reviews]. WWOX/FOR/WOX1 possesses two N-terminal WW domains (containing conserved tryptophan residues), a nuclear localization sequence (NLS) between the WW domains, and a C-terminal short chain alcohol dehydrogenase/reductase (SDR) domain. WWOX mRNA may undergo alternative splicing, thereby generating at least 8 mRNAs mainly coding for proteins with altered SDR domain sequences [4]. Several protein isoforms have been identified [4]. Nonetheless, presence of specific protein isoforms in normal and cancerous tissues remains to be established.WWOX/FOR/WOX1 is considered as a candidate tumor supp
Complement C1q Activates Tumor Suppressor WWOX to Induce Apoptosis in Prostate Cancer Cells  [PDF]
Qunying Hong, Chun-I Sze, Sing-Ru Lin, Ming-Hui Lee, Ruei-Yu He, Lori Schultz, Jean-Yun Chang, Shean-Jen Chen, Robert J. Boackle, Li-Jin Hsu, Nan-Shan Chang
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005755
Abstract: Background Tissue exudates contain low levels of serum complement proteins, and their regulatory effects on prostate cancer progression are largely unknown. We examined specific serum complement components in coordinating the activation of tumor suppressors p53 and WWOX (also named FOR or WOX1) and kinases ERK, JNK1 and STAT3 in human prostate DU145 cells. Methodology/Principal Findings DU145 cells were cultured overnight in 1% normal human serum, or in human serum depleted of an indicated complement protein. Under complement C1q- or C6-free conditions, WOX1 and ERK were mainly present in the cytoplasm without phosphorylation, whereas phosphorylated JNK1 was greatly accumulated in the nuclei. Exogenous C1q rapidly restored the WOX1 activation (with Tyr33 phosphorylation) in less than 2 hr. Without serum complement C9, p53 became activated, and hyaluronan (HA) reversed the effect. Under C6-free conditions, HA induced activation of STAT3, an enhancer of metastasis. Notably, exogenous C1q significantly induced apoptosis of WOX1-overexpressing DU145 cells, but not vehicle-expressing cells. A dominant negative and Y33R mutant of WOX1 blocked the apoptotic effect. C1q did not enhance p53-mediated apoptosis. By total internal reflection fluorescence (TIRF) microscopy, it was determined that C1q destabilized adherence of WOX1-expressing DU145 cells by partial detaching and inducing formation of clustered microvilli for focal adhesion particularly in between cells. These cells then underwent shrinkage, membrane blebbing and death. Remarkably, as determined by immunostaining, benign prostatic hyperplasia and prostate cancer were shown to have a significantly reduced expression of tissue C1q, compared to age-matched normal prostate tissues. Conclusions/Significance We conclude that complement C1q may induce apoptosis of prostate cancer cells by activating WOX1 and destabilizing cell adhesion. Downregulation of C1q enhances prostate hyperplasia and cancerous formation due to failure of WOX1 activation.
microRNA-222 Targeting PTEN Promotes Neurite Outgrowth from Adult Dorsal Root Ganglion Neurons following Sciatic Nerve Transection  [PDF]
Songlin Zhou, Dingding Shen, Yongjun Wang, Leilei Gong, Xiaoyan Tang, Bin Yu, Xiaosong Gu, Fei Ding
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044768
Abstract: Dorsal root ganglia (DRG) neurons spontaneously undergo neurite growth after nerve injury. MicroRNAs (miRNAs), as small, non-coding RNAs, negatively regulate gene expression in a variety of biological processes. The roles of miRNAs in the regulation of responses of DRG neurons to injury stimuli, however, are not fully understood. Here, microarray analysis was performed to profile the miRNAs in L4-L6 DRGs following rat sciatic nerve transection. The 26 known miRNAs were differentially expressed at 0, 1, 4, 7, 14 d post injury, and the potential targets of the miRNAs were involved in nerve regeneration, as analyzed by bioinformatics. Among the 26 miRNAs, microRNA-222 (miR-222) was our research focus because its increased expression promoted neurite outgrowth while it silencing by miR-222 inhibitor reduced neurite outgrowth. Knockdown experiments confirmed that phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a major inhibitor of nerve regeneration, was a direct target of miR-222 in DRG neurons. In addition, we found that miR-222 might regulate the phosphorylation of cAMP response element binding protein (CREB) through PTEN, and c-Jun activation might enhance the miR-222 expression. Collectively, our data suggest that miR-222 could regulate neurite outgrowth from DRG neurons by targeting PTEN.
Loss of wwox expression in zebrafish embryos causes edema and alters Ca2+ dynamics  [PDF]
Yusuke Tsuruwaka,Masataka Konishi,Eriko Shimada
PeerJ , 2015, DOI: 10.7717/peerj.727
Abstract: We investigated the role of the WW domain-containing oxidoreductase (wwox) gene in the embryonic development of zebrafish, with particular emphasis on intracellular Ca2+ dynamics because Ca2+ is an important intracellular messenger. Comparisons between zebrafish wwox and human WWOX sequences identified highly conserved domain structures. wwox was expressed in developing heart tissues in the zebrafish embryo. Moreover, wwox knockdown induced pericardial edema with similarities to conditions observed in human breast cancer. The wwox knockdown embryos with the edema died within a week. High Ca2+ levels were observed at the boundary between the edema and yolk in wwox knockdown embryos.
Stability of Sensory and Motor Neurons in Transection of Their Peripheral Processes in Sciatic Nerve  [PDF]
L.B. Timofeeva,N.V. Blagova,A.G. Velichanskaya,I.L. Ermolin
Sovremennye Tehnologii v Medicine , 2011,
Abstract: The aim of the investigation is to study posttraumatic survival in population of sensory (SN) and motor (MN) neurons and their size groups within 30—300 days after sciatic nerve transection in dynamics. Materials and Methods. There was used a method of retrograde marking by fluorescent dye Mini-Ruby for quantitative detection of survival neurons in SN and MN populations forming rat’s sciatic nerve. Research materials were spinal ganglions (SG) and spinal segments (SS) L4—L6.Conclusion. Posttraumatic death in SN and MN populations after sciatic nerve transection is asynchronous, a sensory part, as a less stable, being a leading one since subjected to earlier degeneration. The death of SN within all periods of the experiment goes before the elimination of MN, and the stabilization of sensory-motor neuron ratio occurs only on the 150th day. Later the imbalance in the relationship appears resulting in a new wave of degeneration among MN indicating incompleteness of a posttraumatic process by the 300th day. As a result, in SN population only 31.47% of nerve cells survive, and in MN population — 40.41%.
Identification and functional annotation of novel microRNAs in the proximal sciatic nerve after sciatic nerve transection
ShiYing Li,Bin Yu,YongJun Wang,DengBing Yao,ZhanHu Zhang,XiaoSong Gu
Science China Life Sciences , 2011, DOI: 10.1007/s11427-011-4213-7
Abstract: The peripheral nervous system is able to regenerate after injury, and regeneration is associated with the expression of many genes and proteins. MicroRNAs are evolutionarily conserved, small, non-coding RNA molecules that regulate gene expression at the level of translation. In this paper, we focus on the identification and functional annotation of novel microRNAs in the proximal sciatic nerve after rat sciatic nerve transection. Using Solexa sequencing, computational analysis, and quantitative reverse transcription PCR verification, we identified 98 novel microRNAs expressed on days 0, 1, 4, 7, and 14 after nerve transection. Furthermore, we predicted the target genes of these microRNAs and analyzed the biological processes in which they were involved. The identified biological processes were consistent with the known time-frame of peripheral nerve injury and repair. Our data provide an important resource for further study of the role and regulation of microRNAs in peripheral nerve injury and regeneration.
creb研究进展  [PDF]
余瑞元,王燕峰,徐长法
中国生物工程杂志 , 2003,
Abstract: creb是camp应答元件结合蛋白(campresponseelementbindingprotein)的简称,它于80年代后期被发现。creb由341个氨基酸残基组成,分子量43000。分子结构分两个区域,n端区域与调节转录的功能有关,c端区域是与启动子结合的部位。creb是crebatf家族中的一个成员,它包括8种分子亚型,其中crebα和crebδα最为重要。creb是一种细胞核内调控因子,它通过自身磷酸化实现调节转录的功能。creb与学习记忆分子神经机制的关系特别受到注意。creb能促进果蝇和小鼠等动物长时程记忆的形成。开展对creb在人类大脑记忆活动中功能的研究,是分子神经生物学家感兴趣的课题。
Generation and Characterization of Mice Carrying a Conditional Allele of the Wwox Tumor Suppressor Gene  [PDF]
John H. Ludes-Meyers,Hyunsuk Kil,Jan Parker-Thornburg,Donna F. Kusewitt,Mark T. Bedford,C. Marcelo Aldaz
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007775
Abstract: WWOX, the gene that spans the second most common human chromosomal fragile site, FRA16D, is inactivated in multiple human cancers and behaves as a suppressor of tumor growth. Since we are interested in understanding WWOX function in both normal and cancer tissues we generated mice harboring a conditional Wwox allele by flanking Exon 1 of the Wwox gene with LoxP sites. Wwox knockout (KO) mice were developed by breeding with transgenic mice carrying the Cre-recombinase gene under the control of the adenovirus EIIA promoter. We found that Wwox KO mice suffered from severe metabolic defect(s) resulting in growth retardation and all mice died by 3 wk of age. All Wwox KO mice displayed significant hypocapnia suggesting a state of metabolic acidosis. This finding and the known high expression of Wwox in kidney tubules suggest a role for Wwox in acid/base balance. Importantly, Wwox KO mice displayed histopathological and hematological signs of impaired hematopoeisis, leukopenia, and splenic atrophy. Impaired hematopoeisis can also be a contributing factor to metabolic acidosis and death. Hypoglycemia and hypocalcemia was also observed affecting the KO mice. In addition, bone metabolic defects were evident in Wwox KO mice. Bones were smaller and thinner having reduced bone volume as a consequence of a defect in mineralization. No evidence of spontaneous neoplasia was observed in Wwox KO mice. We have generated a new mouse model to inactivate the Wwox tumor suppressor gene conditionally. This will greatly facilitate the functional analysis of Wwox in adult mice and will allow investigating neoplastic transformation in specific target tissues.
Conditional Wwox Deletion in Mouse Mammary Gland by Means of Two Cre Recombinase Approaches  [PDF]
Brent W. Ferguson, Xinsheng Gao, Hyunsuk Kil, Jaeho Lee, Fernando Benavides, Martin C. Abba, C. Marcelo Aldaz
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036618
Abstract: Loss of WWOX expression has been reported in many different cancers including breast cancer. Elucidating the function of this gene in adult tissues has not been possible with full Wwox knockout models. Here we characterize the first conditional models of Wwox ablation in mouse mammary epithelium utilizing two transgenic lines expressing Cre recombinase, keratin 5-Cre (BK5-Cre) and MMTV-Cre. In the BK5-Cre model we observed very efficient Wwox ablation in KO mammary glands. However, BK5-Cre Wwox KO animals die prematurely for unknown reasons. In the MMTV-Cre model we observed significant ablation of Wwox in mammary epithelium with no effect on survival. In both of these models we found that Wwox deletion resulted in impaired mammary branching morphogenesis. We demonstrate that loss of Wwox is not carcinogenic in our KO models. Furthermore, no evidence of increase proliferation or development of premalignant lesions was observed. In none of the models did loss of a single Wwox allele (i.e. haploinsufficiency) have any observable phenotypic effect in mammary gland. To better understand the function of Wwox in the mammary gland, transcriptome profiling was performed. We observed that Wwox ablation results in the deregulation of genes involved in various cellular processes. We found that expression of the non-canonical Wnt ligand, Wnt5a, was significantly upregulated in Wwox KO mammary epithelium. Interestingly, we also determined that components of the Jak/Stat3 signaling pathway were upregulated in KO mice and this correlated with a very robust increase in phospho-Stat3 signaling, which warrants further testing. Even though the loss of Wwox expression in breast and other cancers is very well documented, our findings suggest that Wwox does not act as a classical tumor suppressor as previously thought.
WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome
María I Nunez, Daniel G Rosen, John H Ludes-Meyers, Martín C Abba, Hyunsuk Kil, Robert Page, Andres JP Klein-Szanto, Andrew K Godwin, Jinsong Liu, Gordon B Mills, C Marcelo Aldaz
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-64
Abstract: We performed WWOX protein expression analyses by means of immunobloting and immunohistochemistry on normal ovaries and specific human ovarian carcinoma Tissue Microarrays (n = 444). Univariate analysis of clinical-pathological parameters based on WWOX staining was determined by χ2 test with Yates' correction. The basic significance level was fixed at p < 0.05.Immunoblotting analysis from normal ovarian samples demonstrated consistently strong WWOX expression while 37% ovarian carcinomas showed reduced or undetectable WWOX protein expression levels. The immunohistochemistry of normal human ovarian tissue sections confirmed strong WWOX expression in ovarian surface epithelial cells and in epithelial inclusion cysts within the cortex. Out of 444 ovarian carcinoma samples analyzed 30% of tumors showed lack of or barely detectable WWOX expression. The remaining ovarian carcinomas (70%) stained moderately to strongly positive for this protein. The two histotypes showing significant loss of WWOX expression were of the Mucinous (70%) and Clear Cell (42%) types. Reduced WWOX expression demonstrated a significant association with clinical Stage IV (FIGO) (p = 0.007), negative Progesterone Receptor (PR) status (p = 0.008) and shorter overall survival (p = 0.03).These data indicate that WWOX protein expression is highly variable among ovarian carcinoma histotypes. It was also observed that subsets of ovarian tumors demonstrated loss of WWOX expression and is potentially associated with patient outcome.The WWOX gene, originally cloned by our laboratory, spans a genomic region greater than 1 Mb in size and is the second most common chromosomal fragile site, FRA16D (16q23) [1,2]. Abnormalities affecting WWOX at the genomic and expression level have been reported in numerous neoplasias and cancer derived cell lines including, breast, ovarian, esophageal, lung, stomach, liver, pancreas and hematological malignancies [3-12]. We observed that ectopic WWOX expression inhibited anchorag
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