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Yuanyan Wei,
Fengbiao Zhou,
Yuqing Ge,
Hong Chen,
Chunhong Cui,
Dan Liu,
Zhiyuan Yang,
Guoqiang Wu,
Jialin Shen,
Jianxin Gu, Jianhai Jiang
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ABSTRACT: Cell surface carbohydrate chains are widely known to contribute to cell migration, recognition and proliferation. beta1,4-Galactosyltransferase I (beta1,4GalT I) transfers galactose to the terminal N-acetylglucosamine of complex-type N-glycan, and contributes to cell proliferation, differentiation and migration. Here, we identified beta1,4GalT I as a novel target gene of cell cycle regulator E2F1. E2F1 proteins interact with the promoter of the beta1,4GalT I gene in vivo, and E2F1 over-expression stimulates the activity of beta1,4GalT I promoter and the mRNA and protein expression of beta1,4GalT I, and augments the level of beta1, 4-galactosyltion. Site-specific mutagenesis revealed that this region which contains two E2F1 binding site (nt -215 to -207 and +1 to +6) is necessary for beta1,4GalT I activation by E2F1. Furthermore, down-regulation of beta1,4GalT I expression attenuates E2F1-induced DNA synthesis and cell cycle progression as well as the expression of cell-cycle regulator Cyclin D1. Thus, beta1,4GalT I is an important E2F1 target gene that is required for cell cycle progression in mammalian cells, which elicits a new mechanism of cell growth and a new mechanism of beta1,4GalT I transcription.
Journal of biochemistry 09/2010; 148(3):263-71. · 1.95 Impact Factor
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Fengbiao Zhou,
Chunhong Cui,
Yuqing Ge,
Hong Chen,
Qiuping Li,
Zhiyuan Yang,
Guoqiang Wu,
Shuhui Sun,
Kangli Chen,
Jianxin Gu, Jianhai Jiang,
Yuanyan Wei
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ABSTRACT: CD133 is widely used as a marker for the isolation and characterization of normal and cancer stem cells. The dynamic alternation of CD133 glycosylation contributes to the isolation of normal and cancer stem cells, and is supposed to be associated with cell differentiation. Although CD133 has been identified as a N-glycosylated protein, the specific glycosylation status of CD133 remain unclear. Here, we found that CD133 could be sialylated in neural stem cells and glioma-initiating cells, and the sialyl residues attach to CD133 N-glycan terminal via alpha2,3-linkage. Furthermore, desialylation of CD133 by neuraminidase specifically accelerates its degradation in lysosomes-dependent pathway. Taken together, our results characterized CD133 as an alpha2,3-sialylated glycoprotein and revealed that the sialylation modification contributes to the stability of CD133 protein, providing clues to understanding the function of CD133 molecular and to understanding the utility of glycosylated CD133 epitopes in defining neural stem cells and tumour-initiating cells.
Journal of biochemistry 09/2010; 148(3):273-80. · 1.95 Impact Factor
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ABSTRACT: ATF5, a member of ATF/CREB family of b-ZIP transcription factors, is highly expressed in a wide variety of neoplasms and regulates cell differentiation, cell survival and apoptosis. However, the mechanism of human ATF5 transcriptional regulation has not been clarified. Here, we identified the transcription start site of the ATF5 gene, cloned its 5'-flanking region and identified the region -105 to +3 relative to the transcription start site as that having promoter activity. This region contained potential binding sites for several transcription factors, including EBF1, Sp1 and E2F1. EBF1 transcription factor binds to the ATF5 promoter and regulates the ATF5 transcription in an EBF-binding site independent manner. Thus, our studies not only provided molecular basis of ATF5 transcriptional regulation, but also identified ATF5 as a target gene of EBF1 transcription factor.
Journal of biochemistry 08/2010; 148(2):171-8. · 1.95 Impact Factor
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Yuqing Ge,
Fengbiao Zhou,
Hong Chen,
Chunhong Cui,
Dan Liu,
Qiuping Li,
Zhiyuan Yang,
Guoqiang Wu,
Shuhui Sun,
Jianxin Gu,
Yuanyan Wei, Jianhai Jiang
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ABSTRACT: Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was a positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.
Biochemical and Biophysical Research Communications 07/2010; 397(4):711-7. · 2.48 Impact Factor
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ABSTRACT: One of the serious sequelae of chronic hepatitis B virus (HBV) infection is hepatocellular carcinoma (HCC). Among all the proteins encoded by the HBV genome, hepatitis B virus X protein (HBx) is highly associated with the development of HCC. Although Notch1 signaling has been found to exert a tumor-suppressive function during HCC development, the mechanism of interaction between HBx expression and Notch1 signaling needs to be explored. In this study, we report that HBx expression in hepatic and hepatoma cells resulted in decreased endogenous protein levels of Notch1 intracellular domain (ICN1) and messenger RNA levels of its downstream target genes. These effects were due to a reduction of Notch1 cleavage by HBx through the suppression of presenilin1 (Psen1) transcription rather than inhibition of Notch1 transcription or its ligands' expression. Through transient HBx expression, decreased ICN1 resulted in enhanced cell proliferation, induced G1-S cell cycle progression, and blunted cellular senescence in vitro. Furthermore, the effect of blunted senescence-like growth arrest by stable HBx expression through suppression of ICN1 was shown in a nude mouse xenograft transplantation model. The correlation of inhibited Psen1-dependent Notch1 signaling and blunted senescence-like growth arrest was also observed in HBV-associated HCC patient tumor samples. CONCLUSION: Our results reveal a novel function of HBx in blunting senescence-like growth arrest by decreasing Notch1 signaling, which could be a putative molecular mechanism mediating HBV-associated hepatocarcinogenesis.
Hepatology 07/2010; 52(1):142-54. · 11.66 Impact Factor
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Yuanyan Wei,
Fengbiao Zhou,
Yuqing Ge,
Hong Chen,
Chunhong Cui,
Qiuping Li,
Dan Liu,
Zhiyuan Yang,
Guoqiang Wu,
Shuhui Sun,
Jianxin Gu, Jianhai Jiang
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ABSTRACT: Glioma results from unregulated expansion of a self-renewing glioma-initiating cell population. The regulatory pathways which are essential for sustaining the self-renewal of glioma-initiating cells remain largely unknown. Cell surface N-linked oligosaccharides play functional roles in determining cell fate and are associated with glioma malignancy. Previously, we have reported that beta1,4-galactosyltransferase V (beta1,4GalT V) effectively galactosylates the GlcNAcbeta1-->6Man arm of the highly branched N-glycans and positively regulates glioma cell growth. Here, we show that decreasing the expression of beta1,4GalT V by RNA interference in glioma cells attenuated the formation of polylactosamine and inhibited the ability of tumor formation in vivo. Down-regulation of beta1,4GalT V depleted CD133-positive cells in glioma xenograft, and inhibited the self-renewal capacity and the tumorigenic potential of glioma-initiating cells. These data reveal a critical role of beta1,4GalT V in the self-renewal and tumorigenicity of glioma-initiating cells, and indicate that manipulating beta1,4GalT V expression may have therapeutic potential for the treatment of malignant glioma.
Biochemical and Biophysical Research Communications 06/2010; 396(3):602-7. · 2.48 Impact Factor
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Yanzhong Yang,
Weiying Zou,
Xiangfei Kong,
Hanzhou Wang,
Hongliang Zong, Jianhai Jiang,
Yanlin Wang,
Yi Hong,
Yayun Chi,
Jianhui Xie,
Jianxin Gu
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ABSTRACT: The androgen-signaling pathway plays critical roles in normal prostate development, benign prostatic hyperplasia, established prostate cancer, and in prostate carcinogenesis. In this study, we report that trihydrophobin 1 (TH1) is a potent negative regulator to attenuate the androgen signal-transduction cascade through promoting androgen receptor (AR) degradation. TH1 interacts with AR both in vitro and in vivo, decreases the stability of AR, and promotes AR ubiquitination in a ligand-independent manner. TH1 also associates with AR at the active androgen-responsive prostate-specific antigen (PSA) promoter in the nucleus of LNCaP cells. Decrease of endogenous AR protein by TH1 interferes with androgen-induced luciferase reporter expression and reduces endogenous PSA expression. Taken together, these results indicate that TH1 is a novel regulator to control the duration and magnitude of androgen signal transduction and might be directly involved in androgen-related developmental, physiological, and pathological processes.
Journal of Cellular Biochemistry 04/2010; 109(5):1013-24. · 2.87 Impact Factor
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ABSTRACT: One of the most prominent transformation-associated changes in the sugar chains of glycoproteins is an increase in the large N-glycans of cell surface glycoprotein. beta1,4-galactosyltransferase V (beta1,4GalT V) could effectively galactosylate the GlcNAcbeta1-->6 branch which is a marker of glioma. The expression of beta1,4GalT V is increased in the process of glioma development. beta1,4GalT V regulates the invasion, growth in vivo and in vitro of glioma cells. Downregulation of beta1,4GalT V expression increases the sensitivity of malignant glioma cells to DNA damage drugs. Furthermore, beta1,4GalT V regulates Ras and AKT signaling involving in glioma behaviors. Meanwhile, Ras/MAPK and PI3K/AKT signaling pathways are involved in the transcription regulation of beta1,4GalT V gene. E1AF transcription factor, a downstream target of Ras/MAPK and PI3K/AKT signaling pathways, regulates the transcription of beta1,4GalT V in cooperation with Sp1 transcription factor. The contribution of beta1,4GalT V in glioma development is further confirmed in glioma-initiation cells. beta1,4GalT V regulates the self-renewal of glioma-initiation cells. We now present evidence that beta1,4GalT V functions as a positive growth regulator in glioma and might represent a novel target in glioma therapy.
Methods in enzymology 01/2010; 479:3-23. · 1.90 Impact Factor
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Xiangfei Kong,
Huachen Gan,
Yuqing Hao,
Chunming Cheng, Jianhai Jiang,
Yi Hong,
Junwu Yang,
Hao Zhu,
Yayun Chi,
Xiaojing Yun,
Jianxin Gu
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ABSTRACT: CDK11(p58), a CDK11 family Ser/Thr kinase, is a G2/M specific protein and contributed to regulation of cell cycle, transcription and apoptotic signal transduction. Recently, CDK11(p58) has been reported to exert important functions in mitotic process, such as the regulation of bipolar spindle formation and sister chromatid cohesion. Here, we identified p21 activated kinase 1 (PAK1) as a new CDK11(p58) substrate and we mapped a new phosphorylation site of Ser174 on PAK1. By mutagenesis, we created PAK1(174A) and PAK1(174E), which mimic the dephosphorylated and phosphorylated form of PAK1; further analysis showed PAK1(174E) could be recruited to myosin V motor complex through binding to dynein light chain 2 (DLC2). PAK1(174E) could accelerate the mitosis progression in a nocodazole blocked cell model, while PAK1(174A) exhibited an opposite role. Our results indicated PAK1 may serve as a downstream effector of CDK11(p58) during mitosis progression.
Journal of biochemistry 07/2009; 146(3):417-27. · 1.95 Impact Factor
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ABSTRACT: Transcription factor E1AF plays critical roles in neuronal development and tumour metastasis and is regulated by a number of signalling cascades, including the mitogen-activated protein kinase pathways. Accumulated evidence indicted that E1AF might contribute to cell survival in response to environment factors. Here, we provided evidence the cell cycle and apoptosis regulator E2F1 induces E1AF expression at the transcriptional level. DNA damage by etoposide causes E2F1-dependent induction of E1AF expression at transcriptional level. Furthermore, disruption of E1AF expression by E1AF RNAi decreased E2F1-induced apoptosis in response to etoposide. Thus, we conclude that activation of E1AF provides a means for E2F1 to induce cell apoptosis in response to DNA damage.
Journal of Biochemistry 09/2008; 144(4):539-46. · 2.37 Impact Factor
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ABSTRACT: Arsenic trioxide (As2O3) has considerable efficacy in treating solid tumors with induction of apoptosis with largely unknown mechanisms. Posttranslational processing of proteins by glycosylation could have multiple regulating roles in the process of apoptosis. Here, we found that the expression of beta1,6-linked GlcNAc-bearing N-glycans on cell surface protein was gradually decreased after induction of apoptosis by As2O3-treatment. And, As2O3 significantly decreased the protein expression level of beta1,4GalT V, which effectively galactosylates the beta1,6-GlcNAc branch of N-glycans and functions as a positive regulator in glioma development. Furthermore, interfering with the expression of beta1,4GalT V in human glioma cell markedly promoted As2O3-induced cell apoptosis and beta1,4GalT V overexpression significantly reduced As2O3-induced glioma cell apoptosis. Taken together, our results suggested that down-regulation of beta1,4GalT V expression plays an important role in As2O3-induced apoptosis, providing a new mechanism of As2O3-induced cell apoptosis and indicating that inhibitors of beta1,4GalT V may enhance the therapeutic efficiency of As2O3 for malignant glioma.
Cancer Letters 09/2008; 267(1):96-105. · 4.24 Impact Factor
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ABSTRACT: The hepatitis B virus-encoded HBx protein contributes to hepatocarcinogenesis with largely unknown mechanisms. It is widely known that N-linked oligosaccharides on glycoproteins are structurally altered during malignant transformation and these alterations are often associated with malignant transformation of cells. beta-1,4-galactosyltransferase I (GalT I) contributes to the biosynthesis of Galbeta-->4GlcNAc structure in the outer chain moieties of N-glycans.
The difference of GalT I expression between normal liver and hepatoma tissues were investigated; the effect of HBx on GalT I expression was investigated; the role of GalT I in hepatoma cell growth and HBx-induced hepatoma cell growth were investigated.
GalT I was highly expressed in hepatocellular carcinoma and transcriptionally up-regulated by HBx, and functioned as a positive growth regulator in hepatoma cells. Furthermore, decreasing the expression of GalT I in hepatoma cells reduced the ability of tumor formation in vivo and inhibited HBx-induced cell cycle progression.
HBx-induced GalT I expression might contribute to HBx-mediated HCC development and progression.
Journal of Hepatology 09/2008; 49(6):1029-37. · 9.26 Impact Factor
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ABSTRACT: ATF5, a member of activating transcription factor (ATF)/cAMP-response element-binding protein (CREB) family of b-ZIP transcription factors, contributes to neural cell differentiation and is involved in cell apoptosis in response to cisplatin and a number of environment factors. However, the mechanisms governing the regulation of ATF5 protein during apoptosis are largely unknown. In this study we reported that ATF5 protein was a substrate of the ubiquitin-proteasome pathway. Interestingly, the ubiquitin-dependent degradation of exogenous ATF5 protein was independent of lysine residues. Instead, the addition of a large N-terminal enhanced green fluorescence protein tag increased the stability of ATF5 protein, and the free amino acid group of the N-terminal methionine of ATF5 protein was a site for ubiquitinylation, indicating that exogenous ATF5 was degraded via the ubiquitin-proteasome system through N-terminal ubiquitinylation. Furthermore, cisplatin increased ATF5 protein expression via preventing its ubiquitin-dependent degradation, which might be associated with its promoting the nucleus-to-cytoplasm translocation of E2 ubiquitin-conjugating enzyme Cdc34 and reducing the interaction between ATF5 and Cdc34. In summary, a down-regulation of proteasome-mediated degradation of ATF5 might contribute to cisplatin-induced apoptosis, providing a new mechanism of cisplatin-induced apoptosis.
Journal of Biological Chemistry 08/2008; 283(27):18773-81. · 4.77 Impact Factor
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Jianhui Xie,
Tao Wu,
Liang Guo,
Yuanyuan Ruan,
Lei Zhou,
Haiyan Zhu,
Xiaojing Yun,
Yi Hong, Jianhai Jiang,
Yumei Wen,
Jianxin Gu
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ABSTRACT: CLEC-2 was first identified by sequence similarity to C-type lectin-like molecules with immune functions. Recently, human CLEC-2 has been reported as a receptor for the platelet-aggregating snake venom toxin rhodocytin and the endogenous sialoglycoprotein podoplanin. It has also been reported to facilitate the capture of HIV-1. However, investigation of mouse CLEC-2 (mCLEC-2) has little progressed after its identification. In this study, we identified two novel splicing variants of mCLEC-2 derived from omission of exon 2 and 2/4, respectively. These two variants had different expression profiles and subcellular localization from full-length mCLEC-2. Moreover, we observed that full-length mCLEC-2 could be cleaved probably by proteases sensitive to aprotinin and PMSF into a soluble form that partially existed as a disulfide-linked homodimer. The results presented here represent a further advancement toward the understanding of mCLEC-2.
Biochemical and Biophysical Research Communications 07/2008; 371(2):180-4. · 2.48 Impact Factor
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ABSTRACT: Transcription factor E1AF is widely known to play critical roles in tumor metastasis via directly binding to the promoters of genes involved in tumor migration and invasion. Here, we reported for the first time the pro-apoptotic role of E1AF in tumor cells. The expression of E1AF at protein level was obviously increased during Huh-7 and Hep3B cells apoptosis induced by the anticancer agent mithramycin A. E1AF overexpression markedly enhanced mithramycin A-induced Huh-7 cell apoptosis and the expression of pro-apoptotic protein Bax depending on its DNA-binding domain. And, reduction of E1AF inhibited mithramycin A-induced Huh-7 cell apoptosis. Furthermore, reducing the expression of Bax significantly inhibited E1AF-increased Huh-7 cell apoptosis induced by mithramycin A. Taken together, E1AF increases mithramycin A-induced Huh-7 cells apoptosis and Bax expression depending on its DNA-binding domain, indicating that E1AF might contribute to the therapeutic efficiency of mithramycin A for hepatoma.
Archives of Biochemistry and Biophysics 06/2008; 477(1):20-6. · 2.93 Impact Factor
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Jianhai Jiang,
Yuanyan Wei,
Jialin Shen,
Dan Liu,
Xiaoning Chen,
Jin Zhou,
Hongliang Zong,
Xiaojing Yun,
Xiangfei Kong,
Si Zhang,
Yanzhong Yang,
Jianxin Gu
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ABSTRACT: Transcription factor E1AF is widely known to play critical roles in tumor metastasis via directly binding to the promoters of genes involved in tumor migration and invasion. Here, we report for the first time E1AF as a novel binding partner for ubiquitously expressed Sp1 transcription factor. E1AF forms a complex with Sp1, contributes to Sp1 phosphorylation and transcriptional activity, and functions as a mediator between epidermal growth factor and Sp1 phosphorylation and activity. Sp1 functions as a carrier bringing E1AF to the promoter region, thus activating transcription of glioma-related gene for beta1,4-galactosyltransferase V (GalT V; EC 2.4.1.38). Biologically, E1AF functions as a positive invasion regulator in glioma in cooperation with Sp1 partly via up-regulation of GalT V. This report describes a new mechanism of glioma invasion involving a cooperative effort between E1AF and Sp1 transcription factors.
Molecular and cellular biology 01/2008; 27(24):8770-82. · 6.06 Impact Factor
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Hongliang Zong,
Yayun Chi,
Yanlin Wang,
Yanzhong Yang,
Li Zhang,
Haijiao Chen, Jianhai Jiang,
Zejuan Li,
Yi Hong,
Hanzhou Wang,
Xiaojing Yun,
Jianxin Gu
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ABSTRACT: Androgen receptor (AR) is essential for the maintenance of the male reproductive systems and is critical for the carcinogenesis of human prostate cancers (PCas). D-type cyclins are closely related to the repression of AR function. It has been well documented that cyclin D1 inhibits AR function through multiple mechanisms, but the mechanism of how cyclin D3 exerts its repressive role in the AR signaling pathway remains to be identified. In the present investigation, we demonstrate that cyclin D3 and the 58-kDa isoform of cyclin-dependent kinase 11 (CDK11p58) repressed AR transcriptional activity as measured by reporter assays of transformed cells and prostate-specific antigen expression in PCa cells. AR, cyclin D3, and CDK11p58 formed a ternary complex in cells and were colocalized in the luminal epithelial layer of the prostate. AR activity is controlled by phosphorylation at specific sites. We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1). Furthermore, androgen-dependent proliferation of PCa cells was inhibited by cyclin D3/CDK11p58 through AR repression. These data suggest that cyclin D3/CDK11p58 signaling is involved in the negative regulation of AR function.
Molecular and Cellular Biology 11/2007; 27(20):7125-42. · 5.53 Impact Factor
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ABSTRACT: Previous study indicated that beta1,4-galactosyltransferase I (beta1,4GT1) was up-regulated by cycloheximide (CHX) and thus enhanced apoptosis induced by CHX in SMMC-7721 cells. In this study, we reported that constitutively active Akt protein (myr-Akt) inhibited CHX-induced apoptosis in SMMC-7721 cells through down-regulating beta1,4GT1. However, the two PI3K inhibitors LY294002 and wortmannin treatment up-regulated beta1,4GT1 through enhancing Sp1 protein expression and consequently increased CHX-induced SMMC-7721 cells apoptosis. Besides, our results suggested that beta1,4GT1 and cell surface galactose residues synthesized by elevated beta1,4GT1 played an important role in SMMC-7721 cells apoptosis treated with CHX and PI3K inhibitor together. Moreover, we found that CHX accentuated beta1,4GT1 through down-regulating Akt expression to mediate SMMC-7721 cells apoptosis. Taken together, PI3K inhibitors LY294002 and wortmannin up-regulated beta1,4GT1 and enhanced CHX-induced apoptosis in SMMC-7721 cells, which suggested that PI3K inhibitors might have therapeutic potential when combined with CHX in the treatment of hepatoma.
Molecular and Cellular Biochemistry 11/2007; 304(1-2):361-7. · 2.06 Impact Factor
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ABSTRACT: CDK11(p58), a G2/M-specific protein kinase, has been shown to be associated with apoptosis in many cell lines, with largely unknown mechanisms. Our previous study proved that CDK11(p58)-enhanced cycloheximide (CHX)-induced apoptosis in SMMC-7721 hepatocarcinoma cells. Here we report for the first time that ectopic expression of CDK11(p58) down-regulates Bcl-2 expression and its Ser70, Ser87 phosphorylation in CHX-induced apoptosis in SMMC-7721 cells. Overexpression of Bcl-2 counteracts the pro-apoptotic activity of CDK11(p58). Furthermore, we confirm that the kinase activity of CDK11(p58) is essential to the down-regulation of Bcl-2 as well as apoptosis. Taken together, these results demonstrate that CDK11(p58) down-regulates Bcl-2 in pro-apoptosis pathway depending on its kinase activity, which elicits survival signal in hepatocarcinoma cells.
Molecular and Cellular Biochemistry 11/2007; 304(1-2):213-8. · 2.06 Impact Factor
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ABSTRACT: E1AF transcription factor, a member of Ets family, is deregulated in many tumors and widely known to play critical roles in tumor metastasis via directly binding to the promoter of genes involved in tumor migration and invasion. Here, we found that E1AF overexpression promoted breast cancer cell cycle progression and growth in vivo as well as the transcription of cell cycle-related protein Cyclin D3. And, the interference of Cyclin D3 expression by transfecting with Cyclin D3 RNAi inhibited the positive role of E1AF in cell cycle progression. We further showed that decreasing the expression of E1AF by E1AF RNAi reduced Cyclin D3 transcription and expression, and inhibited cell cycle progression that was abrogated by Cyclin D3 overexpression. Taken together, E1AF increases cell cycle progression via upregulation of Cyclin D3 transcription, which elicits a new mechanism of breast cancer growth and a new mechanism of Cyclin D3 transcription.
Biochemical and Biophysical Research Communications 07/2007; 358(1):53-8. · 2.48 Impact Factor
