Disease relevance of CrebA

• Using Drosophila as a model, we show that cAMP-response element-binding protein (CREB) is involved in expanded polyglutamine-induced toxicity [1].
• Our findings, along with the regulation of human Fascin1 (OMIM 602689) by CREB (cAMP response element-binding protein) binding protein, suggest FSCN1 as a candidate gene for developmental brain disorders [2].

High impact information on CrebA

• In the prevailing view, patterned synaptic activity causes kinase-mediated activation of the transcription factor cyclic AMP response-element-binding protein, CREB [3].
• Observations from genetic epistasis and RNA quantification experiments indicate that AP-1 acts upstream of CREB, regulates levels of CREB messenger RNA, and functions at the top of the hierarchy of transcription factors known to regulate long-term plasticity [3].
• Thus, BBF-2 and the DNA sequence to which it binds may be important components of a tissue-specific regulatory mechanism conserved between Drosophila and man [4].
• A number of observations suggest that BBF-2 is involved in fat body-specific expression: Mutations that disrupt BBF-2 binding to two different Adh fat body enhancers in vitro decrease the activity of these enhancers in transgenic flies [4].
• A mutation in the Drosophila homolog of CREB, dCREB2, enhances lethality due to polyglutamine peptides (polyQ), and an additional copy of dCREB2 partially rescues this lethality [1].

Biological context of CrebA

• This high level expression requires two early salivary gland transcription factors; CrebA is required throughout embryogenesis and Fkh is required only during late embryonic stages [5].
• We show that zygotic mutations in several individual secretory pathway genes result in larval cuticle phenotypes nearly identical to those of CrebA mutants [5].
• The DNA-binding domain is more closely related to mammalian CREB than to the AP-1 factors in both sequence homology and specificity of cAMP-responsive element binding [6].
• Based on results from epistasis tests with known dorsal/ventral patterning genes, we propose that dCREB-A encodes a transcription factor that functions near the end of both the DPP- and SPI-signaling cascades to translate the corresponding extracellular signals into changes in gene expression [7].
• Evidence was presented indicating that PGE(1) stimulation was mediated through the binding of cAMP-regulatory element binding protein (CREB) to a prostaglandin-responsive element (PGRE) as well as Sp1 binding to an adjacent Sp1 site [8].

Anatomical context of CrebA

• CrebA regulates secretory activity in the Drosophila salivary gland and epidermis [5].
• In females, dCREB-A is expressed in the ovarian columnar follicle cells, and in males, dCREB-A RNA is seen in the seminal vesicle, ejaculatory duct, and ejaculatory bulb [6].
• In adult female ovaries, dCREB-A is expressed in the stage 9 through stage 11 follicle cell nuclei [9].

Associations of CrebA with chemical compounds

• The protective effects of CREB and heat-shock protein 70 against polyQ are additive, suggesting that targeting multiple pathways may be effective for treatment of polyglutamine diseases [1].
• Sequence analysis demonstrates that this protein is a member of the leucine zipper family of transcription factors. dCREB-A is unusual in that it contains six hydrophobic residue iterations in the zipper domain rather than the four or five commonly found in this group of proteins [6].

Analytical, diagnostic and therapeutic context of CrebA

• In this report, we describe the isolation and initial characterization of a Drosophila protein, dCREB-A, that can bind the somatostatin cyclic AMP (cAMP)-responsive element and is capable of activating transcription in cell culture [6].

References