Cyclic AMP-responsive element-binding protein 1 (CREB1) (CREB1)

Cyclic AMP-responsive element-binding protein 1 (CREB1) is a nuclear transcription factor and a member of the basic leucine zipper (bZIP) protein family [3, 11, 16]. It is activated through phosphorylation at Serine 133 by various upstream kinases, including protein kinase A (PKA), Akt, and p90RSK, in response to diverse cellular signals [4, 6, 14, 15]. Once phosphorylated, CREB1 recruits the coactivator CREB-binding protein (CBP) or p300 to stimulate the transcription of genes containing the cAMP response element (CRE) in their promoters [1, 9, 12, 15]. These target genes are essential for fundamental processes such as cell survival, proliferation, and synaptic plasticity [5, 15, 17].\n\nIn pathological conditions, CREB1 is frequently overexpressed or constitutively activated in a variety of cancers, including leukemias and solid tumors like lung and breast cancer, where it promotes oncogenesis, metastasis, and therapy resistance [1, 6, 11, 15, 18]. Conversely, dysregulation or impaired phosphorylation of CREB1 is implicated in the pathophysiology of neurodegenerative and psychiatric disorders, such as Alzheimer's disease and depression [2, 5, 9, 13]. Current drug development efforts focus on small molecule inhibitors that disrupt the CREB-CBP interaction or prevent CREB from binding to DNA [1, 14, 15]. However, the widespread expression of CREB1 and its vital roles in memory and metabolism present significant safety challenges and therapeutic hurdles [1, 4, 11].

Other names

CREBCREB-1cAMP-responsive element-binding protein 1pCREBPhospho-CREB

Inhibition of the interaction between the CREB kinase-inducible domain (KID) and the coactivator CBP/p300 KIX domain [1, 14, 15]; prevention of CREB binding to DNA cAMP response elements (CRE) [1, 11, 14]; inhibition of upstream kinases involved in CREB phosphorylation such as PKA and RSK [1, 6, 15].