cAMP response element-binding protein 1 (CREB1) (CREB1)

The cAMP response element-binding protein 1 (CREB1) is a ubiquitous transcription factor that serves as the central node of the CREB signaling pathway, integrating various upstream signals to regulate gene expression [1, 10]. It is activated by phosphorylation at Serine 133 by kinases such as protein kinase A (PKA) and mitogen-activated protein kinases (MAPK), which allows it to recruit co-activators like CREB-binding protein (CBP) and bind to cAMP response elements (CRE) in DNA [3, 22]. CREB1 is essential for neuronal plasticity, long-term memory, and cell survival, but its dysregulation is linked to numerous diseases [1, 20]. In many cancers, CREB1 acts as a proto-oncogene, promoting cell proliferation, survival, and metastasis, making it a target for direct small-molecule inhibitors like 666-15 and KG-501 [5, 7]. Conversely, reduced CREB1 activity is associated with neurodegenerative and psychiatric disorders, where indirect activation of the pathway is explored for therapeutic benefit [1, 20]. While targeting this pathway offers significant potential, the ubiquitous expression of CREB1 poses challenges regarding systemic toxicity and off-target effects [3, 5].

Other names

CREB1cAMP-responsive element-binding protein 1Active transcription factor CREB1CREB-1Cyclic AMP-responsive element-binding protein 1

Direct inhibition of CREB-mediated transcription by disrupting the interaction between the CREB basic leucine zipper domain and the KIX domain of the co-activator CREB-binding protein (CBP), or by preventing CREB phosphorylation at Serine 133 [3, 4].