CREB - biochook's diary

Cyclic AMP-responsive element-binding protein 1

Short name=CREB-1 / Short name=cAMP-responsive element-binding protein 1

Gene names: CREB1
Function: Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-133 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.
Subunit structure: Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-133, binds CREBBP By similarity. Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity By similarity. Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Ref.9 Ref.10 Ref.15 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.26 Ref.27
Subcellular location: Nucleus Ref.16.
Post-translational modification: Stimulated by phosphorylation. Phosphorylation of both Ser-133 and Ser-142 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-133 allows CREBBP binding By similarity. CREBL2 positively regulates phosphorylation at Ser-133 thereby stimulating CREB1 transcriptional activity By similarity. Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-133. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-142. Phosphorylation of Ser-142 blocks CREB-mediated transcription even when Ser-133 is phosphorylated. Phosphorylated by CaMK1 By similarity. Phosphorylation of Ser-271 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-133 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Ref.11 Ref.12 Ref.13 Ref.14 Ref.20 Ref.26

Sumoylated with SUMO1. Sumoylation on Lys-304, but not on Lys-285, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization. Ref.16

Involvement in disease: Angiomatoid fibrous histiocytoma (AFH) [MIM:612160]: A distinct variant of malignant fibrous histiocytoma that typically occurs in children and adolescents and is manifest by nodular subcutaneous growth. Characteristic microscopic features include lobulated sheets of histiocyte-like cells intimately associated with areas of hemorrhage and cystic pseudovascular spaces, as well as a striking cuffing of inflammatory cells, mimicking a lymph node metastasis.

Note: The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving CREB1 is found in a patient with angiomatoid fibrous histiocytoma. Translocation t(2;22)(q33;q12) with CREB1 generates a EWSR1/CREB1 fusion gene that is most common genetic abnormality in this tumor type.
A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia (Ref.29).

Sequence similarities: Belongs to the bZIP family. Contains 1 bZIP (basic-leucine zipper) domain. Contains 1 KID (kinase-inducible) domain.

Cyclic AMP-dependent transcription factor ATF-2

Short name=cAMP-dependent transcription factor ATF-2
EC=2.3.1.48

Alternative name(s): Activating transcription factor 2 / Cyclic AMP-responsive element-binding protein 2

Short name=CREB-2
Short name=cAMP-responsive element-binding protein 2
HB16
Histone acetyltransferase ATF2
cAMP response element-binding protein CRE-BP1
Gene names
Name: ATF2
Synonyms: CREB2, CREBP1

Function: Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5'-TGACGTCA-3') or to AP-1 (activator protein 1) consensus sequences (5'-TGACTCA-3'). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro. In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type. Ref.12 Ref.15 Ref.18 Ref.27
Catalytic activity: Acetyl-CoA + [histone] = CoA + acetyl-[histone].
Subunit structure: Binds DNA as a dimer and can form a homodimer in the absence of DNA. Can form a heterodimer with JUN. Heterodimerization is essential for its transcriptional activity. Interacts with SMAD3 and SMAD4. Binds through its N-terminal region to UTF1 which acts as a coactivator of ATF2 transcriptional activity. Interacts with the HK1/VDAC1 complex. Interacts with NBN, MRE11A, XPO1, KAT5 and CUL3. Ref.11 Ref.15 Ref.18 Ref.27 Ref.28
Subcellular location: Nucleus. Cytoplasm. Mitochondrion outer membrane. Note: Shuttles between the cytoplasm and the nucleus and heterodimerization with JUN is essential for the nuclear localization. Localization to the cytoplasm is observed under conditions of cellular stress and in disease states. Localizes at the mitochondrial outer membrane in response to genotoxic stress. Phosphorylation at Thr-52 is required for its nuclear localization and negatively regulates its mitochondrial localization. Co-localizes with the MRN complex in the IR-induced foci (IRIF). Ref.14 Ref.15 Ref.18 Ref.22 Ref.25 Ref.27 Ref.28
Tissue specificity: Ubiquitously expressed, with more abundant expression in the brain.
Domain: The nuclear export signal 1 (N-NES) negatively regulates its nuclear localization and transcriptional activity.
Post-translational modification: Phosphorylation of Thr-69 by MAPK14 and MAPK11, and at Thr-71 by MAPK1/ERK2, MAPK3/ERK1, MAPK11, MAPK12 and MAPK14 in response to external stimulus like insulin causes increased transcriptional activity. Phosphorylated by PLK3 following hyperosmotic stress. Also phosphorylated and activated by JNK and CaMK4. ATM-mediated phosphorylation at Ser-490 and Ser-498 stimulates its function in DNA damage response. Phosphorylation at Ser-62, Thr-73 and Ser-121 activates its transcriptional activity. Phosphorylation at Thr-69 or Thr-71 enhances its histone acetyltransferase (HAT) activity. Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15 Ref.22 Ref.25 Ref.27
Sequence similarities: Belongs to the bZIP family. ATF subfamily. Contains 1 bZIP (basic-leucine zipper) domain. Contains 1 C2H2-type zinc finger.