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. 2010 Jun;10(4):384-91.
doi: 10.2174/156800910791208535.

Targeting CREB for cancer therapy: friend or foe

Xiangshu Xiao  1 , Bingbing X Li, Bryan Mitton, Alan Ikeda, Kathleen M Sakamoto
Affiliations

Targeting CREB for cancer therapy: friend or foe

Xiangshu Xiao et al. Curr Cancer Drug Targets. 2010 Jun.

Abstract

The cyclic-AMP response element-binding protein (CREB) is a nuclear transcription factor activated by phosphorylation at Ser133 by multiple serine/threonine (Ser/Thr) kinases. Upon phosphorylation, CREB binds the transcriptional co-activator, CBP (CREB-binding protein), to initiate CREB-dependent gene transcription. CREB is a critical regulator of cell differentiation, proliferation and survival in the nervous system. Recent studies have shown that CREB is involved tumor initiation, progression and metastasis, supporting its role as a proto-oncogene. Overexpression and over-activation of CREB were observed in cancer tissues from patients with prostate cancer, breast cancer, non-small-cell lung cancer and acute leukemia while down-regulation of CREB in several distinct cancer cell lines resulted in inhibition of cell proliferation and induction of apoptosis, suggesting that CREB may be a promising target for cancer therapy. Although CREB, as a transcription factor, is a challenging target for small molecules, various small molecules have been discovered to inhibit CREB phosphorylation, CREB-DNA, or CREB-CBP interaction. These results suggest that CREB is a suitable transcription factor for drug targeting and therefore targeting CREB could represent a novel strategy for cancer therapy.

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Figures

Fig. 1
Fig. 1
Domain structure of rat CREB. The basic leucine zipper (bZIP) is located at the C-terminus for DNA binding and homodimerization or heterodimerization with other bZIP family members. The kinase-inducible domain (KID) is the inducible activation domain activated by phosphorylation at Ser133. The glutamine rich regions [Q1 and Q2 or constitutive activation domain (CAD)] are the basal transcriptional activation domains. Human CREB lacks the α domain, which forms a presumed amphipathic α-helix to regulate the transcription activity of CREB.
Fig. 2
Fig. 2
Multiple signaling pathways activate CREB by phosphorylation. Illustrated are potential points of intervention by chemical inhibitors: 1) inhibition of kinases; 2) inhibition of CREB-CRE interaction; and 3) inhibition of CREB-CBP interaction.
Fig. 3
Fig. 3
Cancer cells bear higher apoptotic stress than normal cells. Normal cells (left) maintain a homeostasis with low levels of pro-apoptotic factors and anti-apoptotic factors. Upon aberrant activation of oncogenes, the cells start to accumulate apoptotic stress (middle) and most of the cells will die. However, a small percentage of the cells will survive through activation or inactivation of other cell signaling components (e.g. activation of CREB) resulting in up-regulation of anti-apoptotic factors. These transformed cancer cells (right) will maintain this new cellular homeostasis with overall higher levels of both pro-apoptotic factors and anti-apoptotic factors than their normal counterparts.
Chart 1
Chart 1
Chemical inhibitors of CREB-mediated gene transcription [–59].
See this image and copyright information in PMC

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References

    1. Montminy MR, Bilezikjian LM. Binding of a nuclear-protein to the cyclic-AMP response element of the somatostatin gene. Nature. 1987;328:175–178. - PubMed
    1. Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman RH. Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci USA. 1986;83:6682–6686. - PMC - PubMed
    1. Vinson CR, Sigler PB, McKnight SL. Scissors-grip model for DNA recognition by a family of leucine zipper proteins. Science. 1989;246:911–916. - PubMed
    1. Shaywitz AJ, Greenberg ME. CREB: A stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 1999;68:821–861. - PubMed
    1. Du KY, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem. 1998;273:32377–32379. - PubMed

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