CREB (cAMP response element-binding) proteins are transcription factors which bind to certain DNA sequences called cAMP response elements (CRE) and thereby increase or decrease the transcription of certain genes. CREB is highly related (in structure and function) to CREM (cAMP response element modulator) and ATF-1 (activating transcription factor-1) proteins. CREB proteins are expressed in many animals, including humans.
The following genes encode CREB or CREB-like proteins:
- CREB1 (CREB1)
- CREB2 renamed ATF2 (ATF2)
- CREB3 (CREB3)
- CREB5 (CREB5)
- CREB3L1 (CREB3L1)
- CREB3L2 (CREB3L2)
- CREB3L3 (CREB3L3)
- CREB3L4 (CREB3L4)
Mechanism of action
A typical (albeit somewhat simplified) sequence of events is as follows: a signal arrives at the cell surface, activates the corresponding receptor, which leads to the production of a second messenger such as cAMP or Ca2+, which in turn activates a protein kinase. This protein kinase translocates to the cell nucleus, where it activates a CREB protein. The activated CREB protein then binds to a CRE region, and is then bound to by a CBP (CREB binding protein) which coactivates it, allowing it to switch certain genes on or off. The DNA binding of CREB is mediated via its basic leucine zipper domain (bZIP domain) as depicted in the picture.
CREB has many functions in many different organs although most of its functions have been studied in relation to the brain. CREB proteins in neurons are thought to be involved in the formation of long-term memories; this has been shown in the marine snail Aplysia, the fruit fly Drosophila melanogaster, and in rats. They are necessary for the late stage of long term potentiation. There are activator and repressor forms of CREB. Flies genetically engineered to overexpress the inactive form of CREB lose their ability to retain long term memory. CREB is also important for the survival of neurons, as shown in genetically engineered mice, where CREB and CREM were deleted in the brain. If CREB is lost in the whole developing mouse embryo, the mice die immediately after birth, again highlighting the critical role of CREB in promoting survival.
Disturbance of CREB function in brain can contribute to the development and progression of Huntington's Disease. Abnormalities of a protein which interacts with the KID domain of CREB, the CREB binding protein (CBP) is associated with Rubinstein-Taybi syndrome. CREB is also thought to be involved in the growth of some types of cancer.
cAMP response element
The cAMP response element is the response element for CREB. Since the effects of protein kinase A on the synthesis of proteins work by activating CREB, the cAMP response element is responsible for modulating the effects of protein kinase A that work by protein synthesis.
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- Johannessen, M., Pedersen Delghandi, M., and Moens, U. (2004) - What Turns CREB on ? - Cell Signall.; 10:1211-1227. http://www.sigtrans.org/publications/what-turns-creb-on/
- MeSH CREB+Protein
|Transcription factors and intracellular receptors|
|(1) Basic domains|
|(1.1) Basic leucine zipper (bZIP)
||Activating transcription factor (1, 2, 3, 4, 5, 6) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3) • GABPA • MAF (B, F, G, K) • NRL • NRF1 • XBP1
|(1.2) Basic helix-loop-helix (bHLH)
||ATOH1 • AhR • AHRR • ARNT • ASCL1 • BMAL (ARNTL, ARNTL2) • CLOCK • HIF (1A, 3A) • Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) • NEUROD1 • Twist • USF1
||Myc • MITF • SREBP (1, 2)
|(1.6) Basic helix-span-helix (bHSH)
|(2) Zinc finger|
|(2.1) Nuclear receptor (Cys4)
||subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) • subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) • subfamily 3 (Steroid hormone (Estrogen (α, β), Estrogen related (α, β, γ), Androgen, Glucocorticoid, Mineralocorticoid, Progesterone)) • subfamily 4 NUR (NGFIB, NOR1, NURR1) • subfamily 5 (LRH-1, SF1) • subfamily 6 (GCNF) • subfamily 0 (DAX1, SHP)
|(2.2) Other Cys4
||GATA (1, 2, 3, 4, 5, 6)
||General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH: 1, 2) • GLI-Krüppel family (1, 2, 3, YY1) • KLF (2, 4, 5, 6, 10, 11, 12, 13) • Sp1 • zinc finger (3, 35, 43, 146, 148, 165, 217, 268, 281, 350) • Zbtb7 (7A) • ZBT (16, 17, 33)
|(3.1) Homeo domain
||ARX • Homeobox (A1, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C6, C8, C9, C13, D1, D3, D4, D9, D10, D11, D12, D13) • NANOG • NKX (2-1, 2-5, 3-1) • POU domain (PIT-1, BRN-3: 1, 2, Octamer transcription factor: 1, 2, 3/4, 6, 7)
|(3.2) Paired box
||PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)
|(3.3) Fork head / winged helix
||E2F (1, 2, 3, 4, 5) • FOX proteins (C1, C2, E1, G1, H1, L2, M1, N3, O3, O4, P1, P2, P3)
|(3.4) Heat Shock Factors
|(3.5) Tryptophan clusters
||ELF (4, 5) • Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) • MYB
|(3.6) TEA domain
||transcriptional enhancer factor 1, 2
|(4) β-Scaffold factors with|
minor groove contacts
|(4.1) Rel homology region
||NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (5, C1, C2, C3, C4)
||STAT (1, 2, 3, 4, 5, 6)
|(4.4) MADS box
||Mef2 (A, B, C, D) • SRF
|(4.7) High mobility group
||HNF (1A, 1B) • LEF1 • SOX (3, 4, 6, 9, 10, 13, 18) • SRY • SSRP1
|(4.10) Cold-shock domain
||CBF (RUNX1, RUNX2, RUNX3)
| (0) Other|
||HMGA (1, 2)
|(0.3) Pocket domain
||Rb • RBL1 • RBL2
||ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • Rho/Sigma • R-SMAD