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American Journal of Cancer Research (1)
Molecular and Cellular Biology (1)
Wei, Qiou (3)
Jiang, Hong (2)
Baker, Alyson (1)
Chawsheen, Hedy A (1)
Colburn, Nancy H. (1)
Dodge, Lisa K. (1)
Gerard, Matthieu (1)
Mishra, Murli (1)
Miskimins, Robin (1)
Miskimins, W. Keith (1)
Toledano, Michel B. (1)
Wu, Lisha (1)
Young, Matthew R. (1)
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Expression of peroxiredoxin 1 and 4 promotes human lung cancer malignancy
Chawsheen, Hedy A
American Journal of Cancer Research
Members of the Peroxiredoxin (Prx) family are major cellular antioxidants that scavenge hydrogen peroxide and play essential roles in oxidative stress and cell signaling. 2-Cys Prxs, including Prx1, 2, 3 and 4, have been indicated in multiple oncogenic signaling pathways and thus may contribute to various processes of cancer development. The significance of 2-Cys Prxs in lung cancer development and their biological function in signal transduction have not been fully investigated. In this study we analyzed the expression of 2-Cys Prxs in lung cancer, and examined their levels of expression in a variety of cell lines established from human lung normal or cancer tissues. We found that 2-Cys Prxs, in particular, Prx1 and Prx4, were preferentially expressed in cell lines derived from human lung cancer. Through isoform specific knockdown of individual Prx, we demonstrated that Prx1 and Prx4 (but not Prx3) were required for human lung cancer A549 cells to form soft agar colony and to invade through matrigel in culture. Knockdown of Prx1 or Prx4 significantly reduced the activation of c-Jun and repressed the AP-1 mediated promoter activity. In mouse xenograft models, knockdown of Prx4 in A549 cells reduced subcutaneous tumor growth and blocked metastasis formation initiated through tail vein injection. Moreover, overexpression of Prx1 or Prx4 further enhanced the malignancy of A549 cells both in culture and in mouse xenografts in vivo. These data provide an in-depth understanding of the contribution of Prx1 and Prx4 to lung cancer development and are of importance for future development of therapeutic methods that targeting 2-Cys Prxs.
Peroxiredoxin; lung cancer; tumor invasion and metastasis; cell signaling
Loss of sulfiredoxin renders mice resistant to azoxymethane/dextran sulfate sodium-induced colon carcinogenesis
Dodge, Lisa K.
Young, Matthew R.
Toledano, Michel B.
Colburn, Nancy H.
Sulfiredoxin (Srx) is the enzyme that reduces the hyperoxidized inactive form of peroxiredoxins. To study the function of Srx in carcinogenesis in vivo, we tested whether loss of Srx protects mice from cancer development. Srx null mice were generated and colon carcinogenesis was induced by an azoxymethane (AOM) and dextran sulfate sodium (DSS) protocol. Compared with either wild-type (Wt) or heterozygotes, Srx−/− mice had significantly reduced rates in both tumor multiplicity and volume. Mechanistic studies reveal that loss of Srx did not alter tumor cell proliferation; however, increased apoptosis and decreased inflammatory cell infiltration were obvious in tumors from Srx null mice compared with those from Wt control. In addition to the AOM/DSS model, examination of Srx expression in human reveals a tissue-specific expression pattern. Srx expression was also demonstrated in tumors from colorectal cancer patients and the levels of expression were associated with patients’ clinic stages. These data provide the first in vivo evidence that loss of Srx renders mice resistant to AOM/DSS-induced colon carcinogenesis, suggesting that Srx has a critical oncogenic role in cancer development, and Srx may be used as a marker for human colon cancer pathogenicity.
The Sp1 Family of Transcription Factors Is Involved in p27Kip1-Mediated Activation of Myelin Basic Protein Gene Expression
Miskimins, W. Keith
Molecular and Cellular Biology
p27Kip1 levels increase in many cells as they leave the cell cycle and begin to differentiate. The increase in p27Kip1 levels generally precedes the expression of differentiation-specific genes. Previous studies from our laboratory showed that the overexpression of p27Kip1 enhances myelin basic protein (MBP) promoter activity. This activation is specific to p27Kip1. Additionally, inhibition of cyclin-dependent kinase activity alone is not sufficient to increase MBP expression. In this study, we focused on understanding how p27Kip1 can activate gene transcription by using the MBP gene in oligodendrocytes as a model. We show that the enhancement of MBP promoter activity by p27Kip1 is mediated by a proximal region of the MBP promoter that contains a conserved GC box binding sequence. This sequence binds transcription factors Sp1 and Sp3. Increased expression of p27Kip1 increases the level of Sp1 promoter binding to the GC box but does not change the level of Sp3 binding. The binding of Sp1 to this element activates the MBP promoter. p27Kip1 leads to increased Sp1 binding through a decrease in Sp1 protein turnover. Enhancement of MBP promoter activity by an increase in the level of p27Kip1 involves a novel mechanism that is mediated through the stabilization and binding of transcription factor Sp1.
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