CCAAT/Enhancer-Binding Protein Beta
Regulation of CEBP-β
C/EBP-β Growth and Development
During embryogenesis, the C/EBP protein family and especially C/EBP-β is involved in the expression of placenta related genes in the human trophoblast (Bamberger et al. 2004). By direct protein interaction of C/EBP-β with erythroblastosis virus E26 oncogene homologue 2 (Ets-2), trophoblast-specific genes are regulated (Chakrabarty and Roberts 2007).
In mice myoblasts, C/EBP-β is reported to be an important factor to control differentiation being an inhibitor of myogenesis (Marchildon et al. 2012). For instance, C/EBP-β knockout myoblasts differentiated faster and more robust which resulted in muscle fiber hypertrophy. Subsequent overexpression of C/EBP-β in these myoblast inhibited differentiation. These results are in line with the finding that C/EBP-β inhibits myoblast differentiation in cancer cachexia, while loss of C/EBP-β restores this (Marchildon et al. 2015). Furthermore, C/EBP-β stimulation by cyclic adenosine monophosphate phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) results in more myoblast clonal expansion due to inhibited differentiation which continues following drug removal (Lala-Tabbert et al. 2016). In the normal situation, Mouse double minute 2 homolog (Mdm2) is needed to ubiquitinate C/EBP-β and thereby it triggers degradation of C/EBP-β, leading to removal of the differentiation blockade to start the differentiation (Fu et al. 2015) (Fig. 6). These insights in the role of C/EBP-β in myoblast differentiation might therefore be used in further research to aid help people who are suffering of cancer cachexia or muscle disease. Cancer cachexia is thought to result from muscle weight loss that is not replenished by new differentiated myoblast because of increased myoblast cell stress and thereby increased C/EBP-β that subsequent prevents differentiation (Marchildon et al. 2015). In muscle diseases like Duchenne muscular dystrophy (DMD), transplantation of enough myoblast is a problem as the introduced myoblast differentiates too fast. In this case, temporarily inducing C/EBP-β might provide a solution that allows clonal expansion to generate first a substantial number of myoblasts (Lala-Tabbert et al. 2016).
C/EBP-β is also involved in processes related to the central nervous system, as C/EBP- β is important for memory formation and the outgrowth of neurites. Furthermore, C/EBP-β plays a role in inflammatory responses in the microglial cell. In these cells, overexpression of the dominant negative isoform LIP inhibits inflammation-related markers like Nitric oxide synthase 2 (NOS2) and tumor necrosis factor alpha (TNFα). In addition, C/EBP-β knockout mice were significantly less responsive to lipopolysaccharide (LPS) induced inflammation. Therefore, C/EBP-β is thought to possess pro-inflammatory properties. For further reading on the role of C/EBP-β within the nervous system, we refer to Pulido-Salgado et al. (2015) and references herein.
C/EBP-β in Relation to Endoplasmic Reticulum Stress and Inflammation
C/EBP-β induces acute phase proteins like c-reactive protein, glycoprotein, and various cytokines including interleucin-6 (IL-6). These products regulated by C/EBP-β are involved in various inflammatory processes including the regulation of macrophages activation and polarization (Juhas et al. 2015). C/EBP-β is induced during endoplasmic reticulum stress (ER-stress) which is also linked to inflammation (van der Krieken et al. 2015). A nice example is described by Bai et al. (2016), where LPS-induced ER-stress is clearly coupled to a C/EBP-β response. In addition, ER-stress also induces CHOP that might counter the effect of increased C/EBP-β. Furthermore, ATF6 is increased during ER-stress, as ATF6 is a dimeric partner of C/EBP-β; they together are able to alter the cells transcriptional profile during ER-stress. Prolonged ER-stress ultimately leads to cell cycle arrest and may finally result in apoptosis. Taking into account the known roles of C/EBP-β in myoblast and adiposity differentiation, changed levels of C/EBP-β in combination with increased levels of CHOP as often seen during ER-stress are likely to alter differentiation and clonal expansion. In addition, often the LIP/LAP ratio is discussed as important parameter that determines the final outcome (to start differentiation or continue clonal expansion) as it is supposed to reflect the balance between C/EBP-β activation and inactivation (van der Krieken et al. 2015).
C/EBP-β is an important regulator of many biologic processes. Currently, the role of the C/EBP- β gene in mesenchymal cell development and differentiation is most extensively investigated. Nowadays, research on the effect of C/EBP-β and its activation status is focused on the relative amount of LIP and LAP protein that is produced. It is this ratio that should reflect activity or inactivity. However, the use of this ratio alone neglects the many possible other factors that are of influence on C/EBP-β activity, such as posttranslational modifications and proteins like CHOP. Furthermore, the effects of the separate C/EBP- β isoforms are difficult to investigate. Since the products are all derived from a single mRNA transcript, RNA interference would knock out all C/EBP-β isoforms simultaneously. To allow more insight in the mechanisms that the three isoforms are part of, one could overexpress the different isoforms separately, although this might trigger homeostatic mechanisms that might partly counter the overexpression. Altogether, to elucidate the exact mechanism by which C/EBP-β isoforms exert their action, more basic research directed to the three isoforms and their dimerizing partners is warranted.
- Bai Y, Wei Y, Wu L, Wei J, Wang X, Bai Y. C/EBP beta mediates endoplasmic reticulum stress regulated inflammatory response and extracellular matrix degradation in LPS-stimulated human periodontal ligament cells. Int J Mol Sci. 2016;17:385. doi: 10.3390/ijms17030385.CrossRefPubMedPubMedCentralGoogle Scholar
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- Lala-Tabbert N, Fu D, Wiper-Bergeron N. Induction of CCAAT/enhancer-binding protein beta expression with the phosphodiesterase inhibitor isobutylmethylxanthine improves myoblast engraftment into dystrophic muscle. Stem Cells Transl Med. 2016;5:500–10. doi: 10.5966/sctm.2015-0169.CrossRefPubMedPubMedCentralGoogle Scholar