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Transcriptional regulation by the phosphorylation-dependent factor CREB

Key Points

  • The cyclic AMP response element (CRE)-binding protein (CREB) family of activators functions in diverse physiological processes, including the control of cellular metabolism and growth-factor-dependent cell survival.

  • Consistent with these diverse functions, CREB and its paralogues ATF-1 and CREM are activated by phosphorylation in response to a number of signalling pathways, including cAMP, calcium, stress and mitogenic stimuli.

  • Phosphorylation of CREB family members promotes target gene expression through the recruitment of the coactivator CREB-binding protein (CBP) and its paralogue p300.

  • Phosphorylation of CREB at Ser133 in response to cAMP stimulus is sufficient to induce target gene expression, but additional promoter-bound transcription factors are required for induction in response to non-cAMP signals.

  • Cellular discrimination between cAMP and non-cAMP signals (for example, stress and mitogens) occurs at the level of CREB?CBP complex formation. Current evidence supports the presence of a nuclear inhibitor that binds to CREB and blocks CBP recruitment in response to stress or mitogenic stimuli.

Abstract

The transcription factor CREB ? for 'cyclic AMP response element-binding protein' ? functions in glucose homeostasis, growth-factor-dependent cell survival, and has been implicated in learning and memory. CREB is phosphorylated in response to various signals, but how is specificity achieved in these signalling pathways?

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Figure 1: Activation of the cAMP?CREB signalling pathway.
Figure 2: Genomic organization of human members of the CREB family of transcription factors.
Figure 3: Structure of the CREB basic region/leucine zipper domain (amino acids 285?339) bound to the somatostatin CRE.
Figure 4: Structure of the CREB?CBP complex using relevant interaction domains (KID and KIX, respectively).
Figure 5: Signal discrimination at the level of CREB?CBP complex formation.
Figure 6: Models for signal discrimination through CREB.

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Authors and Affiliations

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DATABASE LINKS

CREB

ATF-1

CBP

PKA

CREM

KID

cyclin D1

cyclin A

NGF

BDNF

Bcl-2

PEPCK

cytochrome c

PCNA

c-fos

Pdha-2

TAFII130

KIX

ACT

PKC

Akt

MSK-1

MAPKAP-2

calcium?calmodulin kinase II

calcium?calmodulin kinase IV

EGF

Coffin?Lowry syndrome

rsk-2

TPA

MLL

Kss1

Fus3

FURTHER INFORMATION

Montminy lab

Glossary

SECOND MESSENGER

Molecule that acts within a cell to promote responses to hormonal signals.

PARALOGUE

Genes with related structure and function within the same species.

INTRONIC PROMOTER

DNA sequence located within an intron of a gene that can initiate transcription.

PULMONARY ATELECTASIS

Collapse of alveoli in the lung due to inadequate surfactant production.

SOMATOTROPH HYPOPLASIA

Reduced numbers of growth-hormone-producing cells in the pituitary.

CHONDROCYTES

Collagen-producing cells of cartilage.

K D

Dissociation constant. The reversible breakdown of a complex or a chemical compound into two or more simpler entities.

TATA BOX

(A+T)-rich DNA sequence found in promoters of most eukaryotic genes that promotes binding of the transcriptional apparatus.

TRANSACTIVATION POTENTIAL

Relative ability of a transcription factor to recruit the transcriptional apparatus and stimulate target gene expression.

GENOMIC FOOTPRINTING ASSAY

Technique used to examine occupancy of a particular DNA sequence by transcription factors in vivo.

TAX

HTLV-1 virally encoded protein that promotes leukaemic transformation of T cells by inducing transcription of HTLV-1-encoded genes and certain host genes. Tax does not bind to DNA itself but stimulates gene expression by associating with transcription factors such as CREB and NF-κB.

TFIID

General transcription factor, consisting of the TATA-binding protein (TBP) plus TBP-associated factors (TAFs), which collectively bind to the TATA box. Binding of TFIID to the promoter is generally considered to represent the rate-limiting step in transcriptional activation.

HISTONE ACETYLTRANSFERASE (HAT)

An enzyme that catalyses acetylation of histones and other cellular protein substrates on lysine residues. Acetylation of histones by HATs seems to be crucial for expression of many genes in response to cellular signals.

AMPHIPATHIC

A molecule with both polar and hydrophobic surfaces.

LIM DOMAIN

A cysteine-rich domain that mediates protein?protein interactions.

MIXED LINEAGE LEUKAEMIA

Leukaemias in which cells express both lymphoid and myeloid antigens.

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Mayr, B., Montminy , M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2, 599–609 (2001). https://doi.org/10.1038/35085068

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