The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation

Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Cytokine (Impact Factor: 2.66). 04/2011; 54(1):6-19. DOI: 10.1016/j.cyto.2010.12.019
Source: PubMed


The C/EBP family of proteins represents an important group of bZIP transcription factors that are key to the regulation of essential functions such as cell cycle, hematopoiesis, skeletal development, and host immune responses. They are also intimately associated with tumorigenesis and viral disease. These proteins are regulated at multiple levels, including gene induction, alternative translational initiation, post-translational modification, and protein-protein interaction. This review attempts to integrate recent reports with more than 20 years of previous effort focused on this fascinating collection of regulators.

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    • "LAP2 (34 kDa) is suggested to be a stronger transactivator than the full-length isoform LAP1 (38 kDa). The shorter isoform LIP (20 kDa) lacks the N-terminal transactivation domains and frequently acts as a dominant negative [1] [6]. However, the transactivation potential of these isoforms depends on the LAP/LIP ratio, which is important to modulate cell fate. "
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    ABSTRACT: The CCAAT/enhancer-binding protein beta (C/EBPβ) is a transcription factor expressed in different areas of the brain that regulates the expression of several genes involved in cell differentiation and proliferation. This protein has three isoforms (LAP1, LAP2, and LIP) with different transcription activation potential. The role of female sex hormones in the expression pattern of C/EBPβ isoforms in the rat brain has not yet been described. In this study we demonstrate by western blot that the expression of the three C/EBPβ isoforms changes in different brain areas during the estrous cycle. In the cerebellum, LAP2 content diminished on diestrus and proestrus and LIP content diminished on proestrus and estrus days. In the prefrontal cortex, LIP content was higher on proestrus and estrus days. In the hippocampus, LAP isoforms presented a switch on diestrus day, since LAP1 content was the highest while that of LAP2 was the lowest. The LAP2 isoform was the most abundant one in all the three brain areas. The LAP/LIP ratio changed throughout the cycle and was tissue specific. These results suggest that C/EBPβ isoforms expression changes in a tissue-specific manner in the rat brain due to the changes in sex steroid hormone levels presented during the estrous cycle.
    Full-text · Article · Jun 2015 · International Journal of Endocrinology
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    • "Specifically, in all isoforms of C/EBP, an extension of the zipper dimerization domain, the tail sequence, acts as a motif for protein-protein interactions. For a detailed description of the structure of CCAAT/enhancer binding family members, we refer to two earlier reviews [9] [15]. "
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    ABSTRACT: The prevalence of the metabolic syndrome and underlying metabolic disturbances increase rapidly in developed countries. Various molecular targets are currently under investigation to unravel the molecular mechanisms that cause these disturbances. This is done in attempt to counter or prevent the negative health consequences of the metabolic disturbances. Here, we reviewed the current knowledge on the role of C/EBP-β in these metabolic disturbances. C/EBP-β deletion in mice resulted in downregulation of hepatic lipogenic genes and increased expression of β-oxidation genes in brown adipose tissue. Furthermore, C/EBP-β is important in the differentiation and maturation of adipocytes and is increased during ER stress and proinflammatory conditions. So far, studies were only conducted in animals and in cell systems. The results found that C/EBP-β is an important transcription factor within the metabolic disturbances of the metabolic system. Therefore, it is interesting to examine the potential role of C/EBP-β at molecular and physiological level in humans.
    Full-text · Article · Jan 2015 · BioMed Research International
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    • "C / EBP proteins are a well known recipient of extracellular signals resulting in multiple phosphorylations , acetylations , and SUMOylations ( Nerlov , 2008 ) . Up to eight different phosphorylation sites have been described in C / EBPa ( Tsukada et al . , 2011 ) , and therefore the investigation of the precise phosphorylated forms involved in SHP regulation is complex and out of the scope of this paper ."
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    ABSTRACT: The small heterodimer partner (SHP, NR0B2) is an atypical nuclear receptor that lacks DNA-binding domain. It interacts with and inhibits many transcription factors, affecting key metabolic processes including bile acid, cholesterol, fatty acid and drug metabolism. Our aim was to determine the influence of steatotic drugs and non-alcoholic fatty liver disease (NAFLD) on SHP expression, and to investigate the potential mechanisms. SHP was found repressed by steatotic drugs (valproate, doxycycline, tetracycline and cyclosporin A) in cultured hepatic cells, and in the livers of different animal models of NAFLD: iatrogenic (tetracycline treated rats), genetic (glycine N-methyltransferase deficient mice) and nutritional (mice fed a methionine and choline deficient diet). Among the different transcription factors investigated, CCAAT-enhancer-binding protein α (C/EBPα) showed the strongest dominant-repressive effect on SHP expression in HepG2 and human hepatocytes. Reporter assays revealed that the inhibitory effect of C/EBPα and steatotic drugs co-localize between -340 and -509 bp of the SHP promoter and mutation of a predicted C/EBPα response element at -473 bp abolished SHP repression by both C/EBPα and drugs. Moreover, inhibition of major stress signaling pathways demonstrated that the mitogen-activated protein kinase kinase 1/2 pathway activates while the phosphatidylinositol 3 kinase pathway represses SHP in a C/EBP-dependent manner. We conclude that SHP is downregulated by several steatotic drugs and in advanced NAFLD. These conditions can activate signals that target C/EBPα and consequently repress SHP, thus favoring the progression and severity of NAFLD. The American Society for Pharmacology and Experimental Therapeutics.
    Full-text · Article · Jan 2015 · Molecular pharmacology
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