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Aristidis Moustakas - One of the best experts on this subject based on the ideXlab platform.

  • role of smad proteins and Transcription Factor Sp1 in p21waf1 cip1 regulation by transforming growth Factor β
    Journal of Biological Chemistry, 2000
    Co-Authors: Katerina Pardali, Peter Ten Dijke, Akira Kurisaki, Anita Moren, Dimitris Kardassis, Aristidis Moustakas
    Abstract:

    Abstract Transforming growth Factor-β (TGF-β) inhibits cell cycle progression, in part through up-regulation of gene expression of the p21WAF1/Cip1(p21) cell cycle inhibitor. Previously we have reported that the intracellular effectors of TGF-β, Smad3 and Smad4, functionally cooperate with Sp1 to activate the human p21 promoter in hepatoma HepG2 cells. In this study we show that Smad3 and Smad4 when overexpressed in HaCaT keratinocytes lead to activation of the p21 promoter. Activation requires the binding sites for the ubiquitous Transcription Factor Sp1 on the proximal promoter. Induction of the endogenous HaCaTp21 gene by TGF-β1 is further enhanced after overexpression of Smad3 and Smad4, whereas dominant negative mutants of Smad3 and Smad4 and the inhibitory Smad7 all inhibit p21induction by TGF-β1 in a dose-dependent manner. We show that Sp1 expressed in the Sp1-deficient Drosophila SL-2 cells binds to the proximal p21 promoter sequences, whereas Smad proteins do not. In support of this finding, we show that DNA-binding domain mutants of Smad3 and Smad4 are capable of transactivating the p21 promoter as efficiently as wild type Smads. Co-expression of Smad3 with Smad4 and Sp1 in SL-2 cells or co-incubation of phosphorylated Smad3, Smad4, and Sp1 in vitro results in enhanced binding of Sp1 to the p21 proximal promoter sequences. We demonstrate that Sp1 physically and directly interacts with Smad2, Smad3, and weakly with Smad4 via their amino-terminal (Mad-Homology 1) domain. Finally, by using GAL4 fusion proteins we show that the glutamine-rich sequences in the transactivation domain of Sp1 contribute to the cooperativity with Smad proteins. In conclusion, Smad proteins play important roles in regulation of the p21 gene by TGF-β, and the functional cooperation of Smad proteins with Sp1 involves the physical interaction of these two types of Transcription Factors.

  • c jun transactivates the promoter of the human p21 waf1 cip1 gene by acting as a superactivator of the ubiquitous Transcription Factor Sp1
    Journal of Biological Chemistry, 1999
    Co-Authors: Dimitris Kardassis, Katerina Pardali, Paraskevi Papakosta, Aristidis Moustakas
    Abstract:

    Abstract The cell cycle inhibitor protein p21WAF1/Cip1 (p21) is a critical downstream effector in p53-dependent mechanisms of growth control and p53-independent pathways of terminal differentiation. We have recently reported that the transforming growth Factor-β pathway-specific Smad3 and Smad4 proteins transactivate the human p21 promoter via a short proximal region, which contains multiple binding sites for the ubiquitous Transcription Factor Sp1. In the present study we show that the Sp1-occupied promoter region mediates transactivation of the p21 promoter by c-Jun and the related proteins JunB, JunD, and ATF-2. By using gel electrophoretic mobility shift assays we show that this region does not contain a binding site for c-Jun. In accordance with the DNA binding data, c-Jun was unable to transactivate the p21 promoter when overexpressed in the Sp1-deficientDrosophila-derived SL2 cells. Coexpression of c-Jun and Sp1 in these cells resulted in a strong synergistic transactivation of this promoter. In addition, a chimeric promoter consisting of six tandem high affinity Sp1-binding sites fused with the CAT gene was transactivated by overexpressed c-Jun in HepG2 cells. The above data propose functional cooperation between c-Jun and Sp1. Physical interactions between the two Factors were demonstrated in vitro by using GST-Sp1 hybrid proteins expressed in bacteria andin vitro transcribed-translated c-Jun. The region of c-Jun mediating interaction with Sp1 was mapped within the basic region leucine zipper domain. In vivo, functional interactions between c-Jun and Sp1 were demonstrated using a GAL4-based transactivation assay. Overexpressed c-Jun transactivated a chimeric promoter consisting of five tandem GAL4-binding sites only when coexpressed with GAL4-Sp1-(83–778) fusion proteins in HepG2 cells. By utilizing the same assay, we found that the glutamine-rich segment of the B domain of Sp1 (Bc, amino acids 424–542) was sufficient for c-Jun-induced transactivation of the p21 promoter. In conclusion, our data support a mechanism of superactivation of Sp1 by c-Jun, which is based on physical and functional interactions between these two Transcription Factors on the human p21 and possibly other Sp1-dependent promoters.

Jaffer A Ajani - One of the best experts on this subject based on the ideXlab platform.

  • a high expression level of insulin like growth Factor i receptor is associated with increased expression of Transcription Factor Sp1 and regional lymph node metastasis of human gastric cancer
    Clinical & Experimental Metastasis, 2005
    Co-Authors: Yixing Jiang, Liwei Wang, Xiangdong Le, Jaffer A Ajani, Weida Gong, James L Abbruzzese, Suyun Huang
    Abstract:

    Insulin-like growth Factor I receptor (IGF-IR) is critical to cell survival and growth and altered IGF-IR expression is found in many human cancers. However, its expression and potential role in gastric cancer development and progression has not been explored. The IGF-IR expression level was determined via immunohistochemistry in primary tumor and lymph node metastasis of 86 cases of resected gastric cancer. Relationships of IGF-IR expression with Transcription Factor Sp1 expression and clinicopathological features were analyzed. The impact of altered Sp1 expression on IGF-IR expression and gastric cancer biology was further determined using small inhibitory RNA for Sp1 mRNA. We found that IGF-IR was overexpressed in 62% of the tumor samples when compared with adjacent tumor-free gastric mucosa. Patients with lymph node metastases had strong expression of IGF-IR in both primary and metastatic tumor cells. IGF-IR overexpression in the primary tumor correlated with increased lymph node metastasis. Furthermore, the level of IGF-IR expression directly correlated with that of Sp1, an important Transcription Factor for IGF-IR regulation. Knocking-down of Sp1 expression by small inhibitory RNA led to decreased IGF-IR expression and attenuated growth and metastasis of gastric cancer cells. Therefore, dysregulated expression of IGF-IR and/or Sp1 may contribute to the growth and metastasis of gastric cancer and potentially can be a target of therapeutic intervention.

  • Transcription Factor Sp1 expression is a significant predictor of survival in human gastric cancer
    Clinical Cancer Research, 2003
    Co-Authors: Liwei Wang, Suyun Huang, Zhihai Peng, Xiangdong Le, Tsung Teh Wu, Jaffer A Ajani
    Abstract:

    The Transcription Factor Sp1 regulates the expression of multiple genes. However, its expression and role in human tumor development and progression remain unclear. Using immunohistochemistry, we investigated Sp1 expression patterns in 86 cases of human gastric cancer having various clinicopathologic characteristics, 57 normal gastric tissue specimens, and 53 lymph node metastases. We found that Sp1 protein was expressed predominantly in the nuclei of cells located in the mucous neck region, whereas Sp1 expression was not detected either in the cells located toward the gastric pit (foveolar differentiation) or cells of the glandular epithelium (glandular differentiation). In sharp contrast, strong Sp1 expression was detected in tumor cells, whereas no or very weak Sp1 expression was detected in stromal cells and normal glandular cells surrounding or within the tumors. We also evaluated the effect of Sp1 expression on the survival of patients who have undergone surgical resection. The median survival duration in patients who had a tumor with negative, weak, and strong Sp1 expression was 43, 37, and 8 months, respectively ( P = 0.0075). Next, Sp1 expression, stage, completeness of resection, age, and sex were entered into a Cox proportional hazard model. In multivariate analysis, Sp1 ( P = 0.003) and stage ( P

Liwei Wang - One of the best experts on this subject based on the ideXlab platform.

  • a high expression level of insulin like growth Factor i receptor is associated with increased expression of Transcription Factor Sp1 and regional lymph node metastasis of human gastric cancer
    Clinical & Experimental Metastasis, 2005
    Co-Authors: Yixing Jiang, Liwei Wang, Xiangdong Le, Jaffer A Ajani, Weida Gong, James L Abbruzzese, Suyun Huang
    Abstract:

    Insulin-like growth Factor I receptor (IGF-IR) is critical to cell survival and growth and altered IGF-IR expression is found in many human cancers. However, its expression and potential role in gastric cancer development and progression has not been explored. The IGF-IR expression level was determined via immunohistochemistry in primary tumor and lymph node metastasis of 86 cases of resected gastric cancer. Relationships of IGF-IR expression with Transcription Factor Sp1 expression and clinicopathological features were analyzed. The impact of altered Sp1 expression on IGF-IR expression and gastric cancer biology was further determined using small inhibitory RNA for Sp1 mRNA. We found that IGF-IR was overexpressed in 62% of the tumor samples when compared with adjacent tumor-free gastric mucosa. Patients with lymph node metastases had strong expression of IGF-IR in both primary and metastatic tumor cells. IGF-IR overexpression in the primary tumor correlated with increased lymph node metastasis. Furthermore, the level of IGF-IR expression directly correlated with that of Sp1, an important Transcription Factor for IGF-IR regulation. Knocking-down of Sp1 expression by small inhibitory RNA led to decreased IGF-IR expression and attenuated growth and metastasis of gastric cancer cells. Therefore, dysregulated expression of IGF-IR and/or Sp1 may contribute to the growth and metastasis of gastric cancer and potentially can be a target of therapeutic intervention.

  • Transcription Factor Sp1 expression is a significant predictor of survival in human gastric cancer
    Clinical Cancer Research, 2003
    Co-Authors: Liwei Wang, Suyun Huang, Zhihai Peng, Xiangdong Le, Tsung Teh Wu, Jaffer A Ajani
    Abstract:

    The Transcription Factor Sp1 regulates the expression of multiple genes. However, its expression and role in human tumor development and progression remain unclear. Using immunohistochemistry, we investigated Sp1 expression patterns in 86 cases of human gastric cancer having various clinicopathologic characteristics, 57 normal gastric tissue specimens, and 53 lymph node metastases. We found that Sp1 protein was expressed predominantly in the nuclei of cells located in the mucous neck region, whereas Sp1 expression was not detected either in the cells located toward the gastric pit (foveolar differentiation) or cells of the glandular epithelium (glandular differentiation). In sharp contrast, strong Sp1 expression was detected in tumor cells, whereas no or very weak Sp1 expression was detected in stromal cells and normal glandular cells surrounding or within the tumors. We also evaluated the effect of Sp1 expression on the survival of patients who have undergone surgical resection. The median survival duration in patients who had a tumor with negative, weak, and strong Sp1 expression was 43, 37, and 8 months, respectively ( P = 0.0075). Next, Sp1 expression, stage, completeness of resection, age, and sex were entered into a Cox proportional hazard model. In multivariate analysis, Sp1 ( P = 0.003) and stage ( P

Xiaodong Zhang - One of the best experts on this subject based on the ideXlab platform.

  • hepatitis b virus x protein up regulates c4b binding protein α through activating Transcription Factor Sp1 in protection of hepatoma cells from complement attack
    Oncotarget, 2016
    Co-Authors: Guoxing Feng, Jiong Li, Minying Zheng, Zhe Yang, Shuqin Zhang, Lihong Ye, Weiying Zhang, Xiaodong Zhang
    Abstract:

    // Guoxing Feng 1 , Jiong Li 1 , Minying Zheng 1 , Zhe Yang 1 , Yunxia Liu 1 , Shuqin Zhang 1 , Lihong Ye 2 , Weiying Zhang 1 , Xiaodong Zhang 1 1 State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, P.R. China 2 State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, P.R. China Correspondence to : Xiaodong Zhang, email: zhangxd@nankai.edu.cn Weiying Zhang, email: zhwybao@nankai.edu.cn Keywords: HBx, C4BP, complement attack, HCC Received: November 24, 2015      Accepted: March 14, 2016      Published: March 30, 2016 ABSTRACT Hepatitis B virus X protein (HBx) plays crucial roles in the development of hepatocellular carcinoma (HCC). We previously showed that HBx protected hepatoma cells from complement attack by activation of CD59. Moreover, in this study we found that HBx protected hepatoma cells from complement attack by activation of C4b-binding protein α (C4BPα), a potent inhibitor of complement system. We observed that HBx were positively correlated with those of C4BPα in clinical HCC tissues. Mechanistically, HBx activated the promoter core region of C4BPα, located at -1199/-803nt, through binding to Transcription Factor Sp1. In addition, chromatin immunoprecipitation (ChIP) assays showed that HBx was able to bind to the promoter of C4BPα, which could be blocked by Sp1 silencing. Functionally, knockdown of C4BPα obviously increased the deposition of C5b-9, a complex of complement membrane attack, and remarkably abolished the HBx-induced resistance of hepatoma cells from complement attack in vitro and in vivo . Thus, we conclude that HBx up-regulates C4BPα through activating Transcription Factor Sp1 in protection of liver cancer cells from complement attack. Our finding provides new insights into the mechanism by which HBx enhances protection of hepatoma cells from complement attack.

  • The oncoprotein HBXIP upregulates PDGFB via activating Transcription Factor Sp1 to promote the proliferation of breast cancer cells.
    Biochemical and biophysical research communications, 2013
    Co-Authors: Yingyi Zhang, Yu Zhao, Yu Shen, Xiaoli Cai, Xiaodong Zhang
    Abstract:

    We have reported that the oncoprotein hepatitis B virus X-interacting protein (HBXIP) acts as a novel Transcriptional coactivator to promote proliferation and migration of breast cancer cells. Previously, we showed that HBXIP was able to activate nuclear Factor-κB (NF-κB) in breast cancer cells. As an oncogene, the platelet-derived growth Factor beta polypeptide (PDGFB) plays crucial roles in carcinogenesis. In the present study, we found that both HBXIP and PDGFB were highly expressed in breast cancer cell lines. Interestingly, HBXIP was able to increase Transcriptional activity of NF-κB through PDGFB, suggesting that HBXIP is associated with PDGFB in the cells. Moreover, HBXIP was able to upregulate PDGFB at the levels of mRNA, protein and promoter in the cells. Then, we identified that HBXIP stimulated the promoter of PDGFB through activating Transcription Factor Sp1. In function, HBXIP enhanced the proliferation of breast cancer cells through PDGFB in vitro. Thus, we conclude that HBXIP upregulates PDGFB via activating Transcription Factor Sp1 to promote proliferation of breast cancer cells.

Suyun Huang - One of the best experts on this subject based on the ideXlab platform.

  • a high expression level of insulin like growth Factor i receptor is associated with increased expression of Transcription Factor Sp1 and regional lymph node metastasis of human gastric cancer
    Clinical & Experimental Metastasis, 2005
    Co-Authors: Yixing Jiang, Liwei Wang, Xiangdong Le, Jaffer A Ajani, Weida Gong, James L Abbruzzese, Suyun Huang
    Abstract:

    Insulin-like growth Factor I receptor (IGF-IR) is critical to cell survival and growth and altered IGF-IR expression is found in many human cancers. However, its expression and potential role in gastric cancer development and progression has not been explored. The IGF-IR expression level was determined via immunohistochemistry in primary tumor and lymph node metastasis of 86 cases of resected gastric cancer. Relationships of IGF-IR expression with Transcription Factor Sp1 expression and clinicopathological features were analyzed. The impact of altered Sp1 expression on IGF-IR expression and gastric cancer biology was further determined using small inhibitory RNA for Sp1 mRNA. We found that IGF-IR was overexpressed in 62% of the tumor samples when compared with adjacent tumor-free gastric mucosa. Patients with lymph node metastases had strong expression of IGF-IR in both primary and metastatic tumor cells. IGF-IR overexpression in the primary tumor correlated with increased lymph node metastasis. Furthermore, the level of IGF-IR expression directly correlated with that of Sp1, an important Transcription Factor for IGF-IR regulation. Knocking-down of Sp1 expression by small inhibitory RNA led to decreased IGF-IR expression and attenuated growth and metastasis of gastric cancer cells. Therefore, dysregulated expression of IGF-IR and/or Sp1 may contribute to the growth and metastasis of gastric cancer and potentially can be a target of therapeutic intervention.

  • Transcription Factor Sp1 expression is a significant predictor of survival in human gastric cancer
    Clinical Cancer Research, 2003
    Co-Authors: Liwei Wang, Suyun Huang, Zhihai Peng, Xiangdong Le, Tsung Teh Wu, Jaffer A Ajani
    Abstract:

    The Transcription Factor Sp1 regulates the expression of multiple genes. However, its expression and role in human tumor development and progression remain unclear. Using immunohistochemistry, we investigated Sp1 expression patterns in 86 cases of human gastric cancer having various clinicopathologic characteristics, 57 normal gastric tissue specimens, and 53 lymph node metastases. We found that Sp1 protein was expressed predominantly in the nuclei of cells located in the mucous neck region, whereas Sp1 expression was not detected either in the cells located toward the gastric pit (foveolar differentiation) or cells of the glandular epithelium (glandular differentiation). In sharp contrast, strong Sp1 expression was detected in tumor cells, whereas no or very weak Sp1 expression was detected in stromal cells and normal glandular cells surrounding or within the tumors. We also evaluated the effect of Sp1 expression on the survival of patients who have undergone surgical resection. The median survival duration in patients who had a tumor with negative, weak, and strong Sp1 expression was 43, 37, and 8 months, respectively ( P = 0.0075). Next, Sp1 expression, stage, completeness of resection, age, and sex were entered into a Cox proportional hazard model. In multivariate analysis, Sp1 ( P = 0.003) and stage ( P