cAMP responsive element binding protein 1-Nuclear factor erythroid 2-related factor 2 signaling pathway (CREB1-NRF2 pathway)

The cAMP responsive element binding protein 1 (CREB1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway is a critical cytoprotective axis that regulates the antioxidant response and survival of mesenchymal stem cells (MSCs) under oxidative stress (PubMed: 28935314). CREB1 (UniProt: P16220) acts as an upstream regulator that can bind to the promoter region of the NFE2L2 gene, enhancing the expression of NRF2 (UniProt: Q16237). Once activated, NRF2 translocates to the nucleus and induces the expression of various antioxidant enzymes, such as heme oxygenase-1 (HO-1) and superoxide dismutase (SOD), which protect MSCs from apoptosis and senescence (PubMed: 31430475). This pathway is particularly relevant in regenerative medicine, where the survival and functional integrity of transplanted MSCs are often compromised by the harsh, oxidative microenvironment of injured tissues (PubMed: 27503300). Pharmacological modulation of this pathway, using agents like melatonin or NRF2 activators such as dimethyl fumarate, is being explored to enhance the therapeutic efficacy of MSC-based therapies in conditions like myocardial infarction and neurodegenerative diseases (PubMed: 28935314, PubChem: 637568).

Other names

CREB1-NFE2L2 axisCREB-NRF2 signalingCREB-mediated NRF2 activationCREB-NRF2-HO-1 pathway

The mechanism involves the phosphorylation of CREB1, which then binds to the cAMP response element (CRE) in the NRF2 (NFE2L2) promoter, driving its transcription (PubMed: 28935314). Increased NRF2 protein levels lead to its translocation into the nucleus, where it binds to Antioxidant Response Elements (ARE) to initiate the transcription of cytoprotective genes like HO-1 and NQO1 (PubMed: 31430475).