skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Overexpression of ABIN-2, a negative regulator of NF-{kappa}B, delays liver regeneration in the ABIN-2 transgenic mice

Abstract

Activation of NF-{kappa}B is one of the earliest responses at the start of liver regeneration, and is required for hepatocyte cell cycle progression. The A20-binding inhibitor of NF-{kappa}B activation-2, ABIN-2, is an inhibitor of NF-{kappa}B. However, its effects on hepatocyte cell cycle progression are not known and its involvement in liver regeneration has not been explored. In this study, the temporal expression pattern of the mouse ABIN-2 was studied during liver regeneration induced by partial hepatectomy. We demonstrate that ABIN-2 is rapidly and transiently induced, and expression peaked at around 8 h post-hepatectomy. To test that the inducible expression of ABIN-2 serves to regulate NF-{kappa}B during liver regeneration, transgenic mice overexpressing human ABIN-2 protein in the liver were generated. Our transgenic data demonstrated that overexpression of ABIN-2 inhibited NF-{kappa}B nuclear translocation, which peaked at around 2-4 h post-hepatectomy, and this led to an impairment of the G1/S transition as well as a delay in hepatocyte cell cycle progression of the regenerating liver. In addition, overexpression of ABIN-2 specifically inhibited endogenous ABIN-2 mRNA induction, suggesting a negative feedback mechanism for ABIN-2 expression. In conclusion, ABIN-2 may function as a negative regulator that downregulates NF-{kappa}B activation during liver regeneration.

Authors:
 [1];  [2];  [3];  [3];  [4];  [5]
  1. Faculty of Life Sciences and Institute of Genetics, National Yang-Ming University, Taipei, Taiwan (China)
  2. Department of Life Science, Chang Gung University, Taoyuan, Taiwan (China)
  3. (China)
  4. Laboratory Animal Center, Tzu-Chi University, Hualien, Taiwan (China)
  5. Faculty of Life Sciences and Institute of Genetics, National Yang-Ming University, Taipei, Taiwan (China) and Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan (China) and Division of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Taiwan (China). E-mail: tftsai@ym.edu.tw
Publication Date:
OSTI Identifier:
20798875
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 342; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2006.01.114; PII: S0006-291X(06)00061-1; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL REGENERATION; CELL CYCLE; HEPATECTOMY; LIVER; PROTEINS; TRANSGENIC MICE; TRANSLOCATION

Citation Formats

Li, C.-C., Chou, C.-K., Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan, Division of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Taiwan, Wang, M.-H., and Tsai, T.-F. Overexpression of ABIN-2, a negative regulator of NF-{kappa}B, delays liver regeneration in the ABIN-2 transgenic mice. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2006.01.114.
Li, C.-C., Chou, C.-K., Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan, Division of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Taiwan, Wang, M.-H., & Tsai, T.-F. Overexpression of ABIN-2, a negative regulator of NF-{kappa}B, delays liver regeneration in the ABIN-2 transgenic mice. United States. doi:10.1016/j.bbrc.2006.01.114.
Li, C.-C., Chou, C.-K., Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan, Division of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Taiwan, Wang, M.-H., and Tsai, T.-F. Fri . "Overexpression of ABIN-2, a negative regulator of NF-{kappa}B, delays liver regeneration in the ABIN-2 transgenic mice". United States. doi:10.1016/j.bbrc.2006.01.114.
@article{osti_20798875,
title = {Overexpression of ABIN-2, a negative regulator of NF-{kappa}B, delays liver regeneration in the ABIN-2 transgenic mice},
author = {Li, C.-C. and Chou, C.-K. and Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan and Division of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Taiwan and Wang, M.-H. and Tsai, T.-F.},
abstractNote = {Activation of NF-{kappa}B is one of the earliest responses at the start of liver regeneration, and is required for hepatocyte cell cycle progression. The A20-binding inhibitor of NF-{kappa}B activation-2, ABIN-2, is an inhibitor of NF-{kappa}B. However, its effects on hepatocyte cell cycle progression are not known and its involvement in liver regeneration has not been explored. In this study, the temporal expression pattern of the mouse ABIN-2 was studied during liver regeneration induced by partial hepatectomy. We demonstrate that ABIN-2 is rapidly and transiently induced, and expression peaked at around 8 h post-hepatectomy. To test that the inducible expression of ABIN-2 serves to regulate NF-{kappa}B during liver regeneration, transgenic mice overexpressing human ABIN-2 protein in the liver were generated. Our transgenic data demonstrated that overexpression of ABIN-2 inhibited NF-{kappa}B nuclear translocation, which peaked at around 2-4 h post-hepatectomy, and this led to an impairment of the G1/S transition as well as a delay in hepatocyte cell cycle progression of the regenerating liver. In addition, overexpression of ABIN-2 specifically inhibited endogenous ABIN-2 mRNA induction, suggesting a negative feedback mechanism for ABIN-2 expression. In conclusion, ABIN-2 may function as a negative regulator that downregulates NF-{kappa}B activation during liver regeneration.},
doi = {10.1016/j.bbrc.2006.01.114},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 342,
place = {United States},
year = {Fri Mar 31 00:00:00 EST 2006},
month = {Fri Mar 31 00:00:00 EST 2006}
}
  • Fructose 2,6-bisphosphate (Fru-2,6-P{sub 2}) is an important metabolite that controls glycolytic and gluconeogenic pathways in several cell types. Its synthesis and degradation are catalyzed by the bifunctional enzyme 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK-2). Four genes, designated Pfkfb1-4, codify the different PFK-2 isozymes. The Pfkfb3 gene product, ubiquitous PFK-2 (uPFK-2), has the highest kinase/bisphosphatase activity ratio and is associated with proliferation and tumor metabolism. A transgenic mouse model that overexpresses uPFK-2 under the control of the phosphoenolpyruvate carboxykinase promoter was designed to promote sustained and elevated Fru-2,6-P{sub 2} levels in the liver. Our results demonstrate that in diet-induced obesity, high Fru-2,6-P{sub 2} levelsmore » in transgenic livers caused changes in hepatic gene expression profiles for key gluconeogenic and lipogenic enzymes, as well as an accumulation of lipids in periportal cells, and weight gain.« less
  • Research highlights: {yields} CREG protected MSCs from tumor necrosis factor-{alpha} (TNF-{alpha}) induced apoptosis. {yields} CREG inhibits the phosphorylation of I{kappa}B{alpha} and prevents the activation of NF-{kappa}B. {yields} CREG inhibits NF-{kappa}B nuclear translocation and pro-apoptosis protein transcription. {yields} CREG anti-apoptotic effect involves inhibition of the death receptor pathway. {yields} p53 is downregulated by CREG via NF-{kappa}B pathway under TNF-{alpha} stimulation. -- Abstract: Bone marrow-derived mesenchymal stem cells (MSCs) show great potential for therapeutic repair after myocardial infarction. However, poor viability of transplanted MSCs in the ischemic heart has limited their use. Cellular repressor of E1A-stimulated genes (CREG) has been identified asmore » a potent inhibitor of apoptosis. This study therefore aimed to determine if rat bone marrow MSCs transfected with CREG-were able to effectively resist apoptosis induced by inflammatory mediators, and to demonstrate the mechanism of CREG action. Apoptosis was determined by flow cytometric and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays. The pathways mediating these apoptotic effects were investigated by Western blotting. Overexpression of CREG markedly protected MSCs from tumor necrosis factor-{alpha} (TNF-{alpha}) induced apoptosis by 50% after 10 h, through inhibition of the death-receptor-mediated apoptotic pathway, leading to attenuation of caspase-8 and caspase-3. Moreover, CREG resisted the serine phosphorylation of I{kappa}B{alpha} and prevented the nuclear translocation of the transcription factor nuclear factor-{kappa}B (NF-{kappa}B) under TNF-{alpha} stimulation. Treatment of cells with the NF-{kappa}B inhibitor pyrrolidine dithiocarbamate (PDTC) significantly increased the transcription of pro-apoptosis proteins (p53 and Fas) by NF-{kappa}B, and attenuated the anti-apoptotic effects of CREG on MSCs. The results of this study indicate that CREG acts as a novel and potent survival factor in MSCs, and may therefore be a useful therapeutic adjunct for transplanting MSCs into the damaged heart after myocardial infarction.« less
  • Highlights: Black-Right-Pointing-Pointer Cisplatin increases acetylation of NF-{kappa}B p65 subunit in HK2 cells. Black-Right-Pointing-Pointer SIRT1 overexpression decreases cisplatin-induced p65 acetylation and -cytotoxicity. Black-Right-Pointing-Pointer Resveratrol decreased cisplatin-induced cell viability through deacetylation of p65. -- Abstract: As the increased acetylation of p65 is linked to nuclear factor-{kappa}B (NF-{kappa}B) activation, the regulation of p65 acetylation can be a potential target for the treatment of inflammatory injury. Cisplatin-induced nephrotoxicity is an important issue in chemotherapy of cancer patients. SIRT1, nicotinamide adenine dinucleotide (NAD{sup +})-dependent protein deacetylase, has been implicated in a variety of cellular processes such as inflammatory injury and the control of multidrug resistancemore » in cancer. However, there is no report on the effect of SIRT1 overexpression on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury. To investigate the effect of SIRT1 in on cisplatin-induced acetylation of p65 subunit of NF-{kappa}B and cell injury, HK2 cells were exposed with SIRT1 overexpression, LacZ adenovirus or dominant negative adenovirus after treatment with cisplatin. While protein expression of SIRT1 was decreased by cisplatin treatment compared with control buffer treatment, acetylation of NF-{kappa}B p65 subunit was significantly increased after treatment with cisplatin. Overexpression of SIRT1 ameliorated the increased acetylation of p65 of NF-{kappa}B during cisplatin treatment and cisplatin-induced cytotoxicity. Further, treatment of cisplatin-treated HK2 cells with resveratrol, a SIRT1 activator, also decreased acetylation of NF-{kappa}B p65 subunit and cisplatin-induced increase of the cell viability in HK2 cells. Our findings suggests that the regulation of acetylation of p65 of NF-{kappa}B through SIRT1 can be a possible target to attenuate cisplatin-induced renal cell damage.« less
  • Nuclear Factor-kappa B (NF-{kappa}B) is a transcription factor essential to the control of cell proliferation, survival, differentiation, immune response, and inflammation. Constitutive NF-{kappa}B activation has been observed in a broad variety of solid tumors and hematological malignancies, which suggests that NF-{kappa}B signaling may perform a critical role in the development of human cancers. Interferon regulatory factor-2 (IRF-2), an antagonistic transcriptional repressor of IRF-1, evidences oncogenic potential, but little is currently known regarding the mechanism underlying the oncogenic activities of IRF-2. In this study, we report that IRF-2 recruits RelA/p65 transcription factors into the nucleus via physical interaction. While the nuclearmore » recruitment of RelA by IRF-2 augments TNF{alpha}-induced NF-{kappa}B dependent transcription, the N-terminal truncated mutant form of IRF-2 inhibits the nuclear localization of RelA, and thus interferes with NF-{kappa}B activation. Furthermore, the knockdown of IRF-2 by IRF-2 siRNA attenuates TNF{alpha}-induced NF-{kappa}B dependent transcription by inhibiting the nuclear localization of RelA. Thus, these results show that IRF-2 regulates NF-{kappa}B activity via the modulation of NF-{kappa}B subcellular localization.« less
  • Highlights: Black-Right-Pointing-Pointer IL-33 as nuclear factor regulated expression of ICAM-1 and VCAM-1. Black-Right-Pointing-Pointer Nuclear IL-33 increased the transcription of NF-{kappa}B p65 by binding to the p65 promoter. Black-Right-Pointing-Pointer Nuclear IL-33 controls NF-{kappa}B-dependent inflammatory responses. -- Abstract: Interleukin (IL)-33, an IL-1 family member, acts as an extracellular cytokine by binding its cognate receptor, ST2. IL-33 is also a chromatin-binding transcriptional regulator highly expressed in the nuclei of endothelial cells. However, the function of IL-33 as a nuclear factor is poorly defined. Here, we show that IL-33 is a novel transcriptional regulator of the p65 subunit of the NF-{kappa}B complex and ismore » involved in endothelial cell activation. Quantitative reverse transcriptase PCR and Western blot analyses indicated that IL-33 mediates the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells basally and in response to tumor necrosis factor-{alpha}-treatment. IL-33-induced ICAM-1/VCAM-1 expression was dependent on the regulatory effect of IL-33 on the nuclear factor (NF)-{kappa}B pathway; NF-{kappa}B p65 expression was enhanced by IL-33 overexpression and, conversely, reduced by IL-33 knockdown. Moreover, NF-{kappa}B p65 promoter activity and chromatin immunoprecipitation analysis revealed that IL-33 binds to the p65 promoter region in the nucleus. Our data provide the first evidence that IL-33 in the nucleus of endothelial cells participates in inflammatory reactions as a transcriptional regulator of NF-{kappa}B p65.« less