Transcriptional and translational control of C/EBPs: The case for “deep” genetics to understand physiological function

Abstract

The complexity of organisms is not simply determined by the number of their genes, but to a large extent by how gene expression is controlled. In addition to transcriptional regulation, this involves several layers of post-transcriptional control, such as translational repression, microRNA-mediated mRNA degradation and translational inhibition, alternative splicing, and the regulated generation of functionally distinct gene products from a single mRNA through alternative use of translation initiation sites. Much progress has been made in describing the molecular basis for these gene regulatory mechanisms. However, it is now a major challenge to translate this knowledge into deeper understanding of the physiological processes, both normal and pathological, that they govern. Using the C/EBP family of transcription factors as an example, the present review describes recent genetic experiments addressing this general problem and discusses how the physiological importance of newly discovered regulatory mechanisms might be determined.

C/EBPβ Is Involved in the Amplification of Early Granulocyte Precursors during Candidemia-Induced “Emergency” Granulopoiesis

“…The expression of C/EBPb is regulated at the transcriptional, translational, and posttranslational levels; posttranslational modifications include phosphorylation and sumoylation (36). We have previously shown that C/EBPb transcripts were upregulated after cytokine stimulation or infection (8).…”

Transcriptional Control of Macrophage Polarization

“…Physiologically, the anti-inflammatory role of C/EBPβ apparent in cardiotoxin-induced muscle injury illustrates that lack of the transcription factor results in failure of injury resolution and ultimate scar formation. 74 Murine models of miR-223 deficiency have suggested a role for this miR in chronic inflammatory disease, including rheumatoid arthritis and type 2 diabetes mellitus. 72 Macrophagespecific deletion of mir-223 results in M1 polarization and delayed M2 polarization after LPS and IL-4 stimulation, respectively.…”

Calcium/Calmodulin-dependent Protein Kinase Kinase 2 Regulates Macrophage-mediated Inflammatory Responses

“…CCAAT/enhancer-binding protein (C/EBP) ␣, ␤, and ␦ are members of a family of basic region-leucine zipper (bZIP) transcription factors that are expressed in macrophages and regulate the expression of cytokine and chemokine genes in response to LPS (27). To explore the effects of CaMKK2 ablation on these critical transcription factors, we evaluated c/EBP mRNA levels in quiescent and LPS-stimulated macrophages.…”

“…4C). These data are of particular interest due to the ability of c/EBP family members to extensively regulate the TLR-induced transcription program of macrophages (27,28).…”