CCAAT-enhancer-binding proteins
CCAAT-enhancer-binding proteins (or C/EBPs) is a
Function
C/EBP proteins interact with the CCAAT (
These proteins are found in
This protein is expressed in the mammalian
Gene transcription
The
Regulation
C/EBPβ function is regulated by multiple mechanisms, including
, and other proteins, leading to a trans-activation potential.Phosphorylation of C/EBPβ can have an activation or a repression effect. For example, phosphorylation of threonine 235 in human C/EBPβ, or of threonine 188 in mouse and rat C/EBPβ, is important for C/EBPβ trans-activation capacity. Phosphorylation(s) of C/EBPβ in its regulatory domain can also modulate its function.
It was shown in C. elegans that multiple cis elements of cebp-1 mRNA 3'UTR interact with mak-2 to upregulate expression of CEBP-1 in neuronal development.[4]
Clinical significance
Role in adipogenesis
C/EBPβ and δ are transiently induced during the early stages of adipocyte differentiation (adipogenesis), while C/EBPα is upregulated during the terminal stages of adipogenesis. In vitro and in vivo studies have demonstrated that each plays an important role in this process. For example, Murine Embryonic Fibroblasts (MEFs) from mice lacking both C/EBPβ and C/EBPδ show impaired adipocyte differentiation in response to adipogenic stimuli.[5] In contrast, ectopic expression of C/EBPβ and δ in 3T3-L1 preadipocytes promotes adipogenesis, even in the absence of adipogenic stimuli.[6][7] C/EBPβ and δ promote adipogenesis, at least in part by inducing the expression of the "master" adipogenic transcription factors C/EBPα and PPARγ.
C/EBPα is required both for adipogenesis and for normal adipocyte function. For example, mice lacking C/EBPα in all tissues except the liver (where it is needed to avoid postnatal lethality) show abnormal adipose tissue formation.[8] Moreover, ectopic expression of C/EBPα in various fibroblast cell lines promotes adipogenesis.[9] C/EBPα probably promotes adipogenesis by inducing the expression of PPARγ.[10]
Role in osteoporosis
C/EBPβ has been found to have a role in the development of
The LAP/LIP balance is determined by the mTOR protein. Inhibition of the expression of mTOR can stop osteoclast activity.[11]
Role in cancer
CCAAT/enhancer-binding proteins are often involved in growth arrest and differentiation, which has been interpreted to suggest that these proteins harbor tumor suppressive activities. However, CCAAT/enhancer-binding protein over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic role. Importantly, however, C/EBPδ acts as a tumor suppressor in pancreatic ductal adenocarcinoma. This is of particular interest since only few tumor suppressors have been identified in the context of pancreatic cancer.[12] The function of CCAAT/enhancer-binding proteins in cancer is thus clearly context dependent but largely tumor suppressive.
Role in neurodegeneration
C/EBPβ levels are increased in cortical samples of Alzheimer's and Parkinson's disease victims at autopsy.[13] Cell culture studies in mice and human microglia lines also find increased C/EBPβ activity associated with pathogenic inflammation and cytokine responses. Downstream analysis of genes regulated by C/EBPβ have significance in immune response, mitochondrial health, and autophagy. Molecular interference of these cellular processes have been shown to play a role in neurodegenerative pathogenesis.[14] Genetic and molecular pathways with degenerative implications involving C/EBPβ and it's homologs are conserved across multiple model organisms including Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio.[14][15] Upstream regulators of C/EBPβ include genes known to be associated with neurodegenerative and neurodevelopmental disease when mutated or dysregulated. This includes a well characterized cellular stress response pathway involving p38 and JNK.[16]
References
- PMID 12578822.
- PMID 12857754.
- PMID 12006103.
- PMID 28673818.
- PMID 9405372.
- PMID 1840554.
- PMID 7531665.
- PMID 11606718.
- PMID 7958846.
- PMID 9367890.
- ^ [1], Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis
- PMID 32906832.
- PMC 3899300.
- ^ PMC 8920508.
- .
- PMC 7460549.
External links
- CCAAT-Enhancer-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)