CrebA

EVOLUTIONARY HOMOLOGS part 1/2

For information on the involvement of mammalian CREB in learning and the interaction of CREB with Creb binding protein (CBP) see CrebB-17A. For information on the targeting of CREB by cAMP dependent Protein kinase A, see in cAMP dependent Protein kinase 1 site.

The S. pombe pcr1 gene encodes a bZIP protein that apparently belongs to the cyclic AMP response element (CRE)-binding protein/activating transcription factor (CREB) family. The deduced pcr1 gene product consists of 171 amino acid residues and is most similar to the mammalian CRE-BP1. The protein is able to bind specifically to the CRE motif in vitro. Pcr1 is included in the major CRE-binding factors present in the S. pombe cell extract. Disruption of the pcr1 gene is not lethal, but the disruptant shows cold-sensitive growth on rich medium. The disruptant is also inefficient in mating and sporulation, though it is not completely sterile. Expression of the ste11 gene, which encodes a key transcription factor for sexual development, is greatly reduced in the disruptant, and overexpression of ste11+ suppresses the deficiency of the pcr1 disruptant in sexual development. It has been shown that expression of ste11 is negatively regulated by cyclic AMP-dependent protein kinase (PKA) and that the loss of PKA activity results in ectopic sexual development. Disruption of pcr1 blocks ectopic sexual development. Disruption of pcr1 reduces expression of fbp1, a glucose-repressible gene negatively regulated by PKA. These results suggest that Pcr1 is a putative transcriptional regulator whose activity may be controlled by PKA. Alternatively, its activity may be independent of PKA. Full induction of ste11 and fbp1 expression requires the function of Pcr1 in addition to elimination of the repression by PKA (Watanabe, 1996).

The atf1+ gene of the fission yeast S. pombe codes for a bZIP domain protein with strong homology to members of the ATF/CREB family of mammalian factors and in vitro binds specifically to ATF/CRE recognition sites. Upon growth to saturation, fission yeast cells exit the mitotic cycle and enter a G0-like stationary phase. However, on rich medium, entry of atf1- cells into stationary phase is restricted and they rapidly lose viability; this does not occur on minimal medium unless cAMP levels are raised. Thus stationary phase entry appears to be regulated negatively by cAMP and positively by Atf1. atf1- cells are also sterile and this sterility appears to be due to a combination of two defects: (1) upon nitrogen starvation the majority of atf1- cells fail to arrest in the G1 phase of the cell cycle, and (2) the induction of ste11+ expression is lost. Thus expression of ste11+ represents a second example of an event that is negatively regulated by the cAMP pathway and positively regulated by Atf1. Despite their close association however, these two regulatory pathways function independently and Atf1 activity is not directly modulated by cAMP levels or mutations that alter the activity of components of the cAMP signaling pathway. Thus Atf1 is a transcription factor that plays an important role in the response of cells to adverse environmental conditions, which is to exit the mitotic cell cycle and then either sexually differentiate or enter a resting state (Takeda, 1995).

The Hydra neuropeptide head activator affects cellular growth and head-specific cellular differentiation during head regeneration and budding. In order to investigate the signal transduction pathway and the regulatory genes involved in these processes, cAMP levels were measured after head activator (HA) treatment. Head activator leads to an increase in cAMP levels at concentrations where effects on nerve cell determination and differentiation are observed. Exposure of intact hydra to a permeable form of cAMP stimulates nerve-cell differentiation and thus mimicks the effect of endogenous head activator. The cAMP response element (CRE) promotes a specific and strong DNA-binding activity that is dramatically enhanced and modified either during early regeneration or after HA treatment. A surprisingly highly conserved hydra gene was identified that encodes the cAMP response element binding protein (CREB), which is involved in this CRE-binding activity. Initiation of regeneration upon wounding provokes an endogenous release of HA which leads to the final differentiation of determined nerve cells. It is proposed that the nerve-cell differentiation observed within the first 4-8 hours of regeneration relies on the agonist effect of head activator on the cAMP pathway, which would in turn modulate the CRE-binding activity of the hydra CREB protein and thus regulate the transcriptional activity of genes involved in regeneration processes (Galliot, 1995).

CREB mutation in mammals

Homozygous mice mutant for CREB appear healthy and exhibit no impairment of growth or development. CREB and two other members of the CREB/ATF family [cAMP response element modulation protein (CREM) and activating transcription factor 1 (ATF1)] appear to form a unique subgroup within this extensive class of transcription factors. Examination of CREM mRNA and protein levels in CREB mutant mice demonstrate overexpression of CREM in all tissues examined, but no change in ATF1 levels. These data demonstrate that CREB is not the sole mediator of cAMP-dependent transcriptional regulation and probably acts in concert with a specific subset of cAMP response element-binding proteins to transduce the cAMP signal; in its absence, these same proteins can compensate for CREB function in vivo (Hummler, 1994).

To define the role of cAMP signaling in gene control, mice were generated with a mutation in the cAMP response element binding protein (CREB) gene. Mice carrying this mutation are viable but show an impairment in memory consolidation. An up-regulation of a CREB isoform was observed that has not been described previously. The new isoform, termed CREB beta, has nearly the same transactivation potential as the other CREB isoforms and is expressed ubiquitously. The up-regulation appears to be due to an increase in alternative splicing or mRNA stability, but not to an increase in transcriptional rate. Due to the relatively low levels of expression in all tissues, the role of this isoform is likely to be minor in the wild-type mouse. However, its dramatic up-regulation in the mutant mouse, together with the specific deficiencies recently observed in these mice, suggest that it has a very specific role in compensating for CREB alpha and delta in some, but not all, areas where CREB function has been implicated. Together with the up-regulation of the cAMP response element modulator protein (CREM) mRNA and protein levels demonstrated previously in CREB mutant mice, it is suggest that the up-regulation of CREB beta may also contribute to compensation within the CREB/ATF family of transcription factors, when CREB delta and CREB alpha are absent (Blendy, 1996).

Activating transcription factor-2 (ATF-2) is a basic region leucine zipper protein whose DNA target sequence is the widely distributed cAMP response element (CRE). Mice carrying a germline mutation in ATF-2 demonstrate unique actions of ATF-2 not duplicated by other ATF/CREB family members. Mutant mice have decreased postnatal viability and growth, with a defect in endochondral ossification at epiphyseal plates similar to human hypochondroplasia. The animals have ataxic gait, hyperactivity and decreased hearing. In the brain, there were reduced numbers of cerebellar Purkinje cells, atrophic vestibular sense organs and enlarged ventricles. Unlike CREB alpha/delta-deficient mice whose main defect is in long-term potentiation, the widespread abnormalities in ATF-2 mutant mice demonstrate its absolute requirement for skeletal and central nervous system development, and for maximal induction of select genes with CRE sites, such as E-selectin (Reimold, 1997).

CREB function in various tissues

Continued: see CrebA Evolutionary homologs part 2/2   |

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