CREB Signaling Mechanisms in Cancer Pathophysiology

The cyclic AMP response element-binding protein (CREB) is a ubiquitous transcription factor that translates diverse extracellular cues into gene expression programmes. Activation of CREB predominantly occurs via phosphorylation at serine 133 by kinases such as protein kinase A, MAPKs and Akt. Phosphorylated CREB recruits transcriptional co-activators, notably CBP/p300, to promoters containing cAMP response elements (CRE) and drives expression of genes governing cell proliferation, survival, differentiation, metabolism and angiogenesis. In malignancy, aberrant CREB expression or constitutive activation has been documented across numerous tumour types and is associated with enhanced growth, metastatic dissemination and resistance to therapy. CREB engages in extensive cross-talk with other oncogenic pathways—including MAPK, hypoxia signalling and epigenetic regulators—thereby integrating environmental stresses and intracellular signals to reshape the tumour microenvironment. Its central role in orchestrating pro-tumourigenic gene networks positions CREB as both a biomarker of disease progression and a promising target for therapeutic intervention.

Research from Nature Portfolio

Recent studies have evaluated the feasibility of pharmacological CREB inhibition in vivo. One foundational investigation described a selective small-molecule antagonist of the CREB–CBP interaction that effectively suppressed CREB-dependent transcription and restrained tumour growth in preclinical models. Treated subjects exhibited no significant alterations in body weight, haematological indices or vital organ histology, demonstrating a favourable tolerability profile. These findings validate the concept of CREB as a druggable target and support the continued development of CREB-directed therapies for cancer.

CREB Signaling Mechanisms in Cancer Pathophysiology publication trend

The graph below shows the total number of articles in creb signaling mechanisms in cancer pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

cAMP response element-binding protein (CREB): A nuclear transcription factor activated by phosphorylation that binds to CRE sequences to regulate gene transcription.

Phosphorylation: A reversible post-translational modification involving addition of a phosphate group, often modulating protein function.

Transcription co-activator: A protein such as CBP or p300 that associates with transcription factors to enhance recruitment of the transcriptional machinery.

cAMP response element (CRE): A specific DNA motif (TGACGTCA) in gene promoters recognised by activated CREB to initiate transcription.

References

1. Multi-faceted regulation of CREB family transcription factors. Frontiers in Molecular Neuroscience (2024).
2. What turns CREB on? And off? And why does it matter?. Cellular and Molecular Life Sciences (2020).
3. Control of CREB expression in tumors: from molecular mechanisms and signal transduction pathways to therapeutic target. Oncotarget (2016).
4. Systemic Inhibition of CREB is Well-tolerated in vivo. Scientific Reports (2016).
5. A Novel Small-Molecule Inhibitor Targeting CREB-CBP Complex Possesses Anti-Cancer Effects along with Cell Cycle Regulation, Autophagy Suppression and Endoplasmic Reticulum Stress. PLOS ONE (2015).
6. Systematical analysis reveals a strong cancer relevance of CREB1-regulated genes. Cancer Cell International (2021).