contributed equally to this workThe CBP co-activator protein possesses an intrinsic acetyltransferase (AT) activity capable of acetylating nucleosomal histones, as well as other proteins such as the transcription factors TFIIE and TFIIF. In addition, CBP associates with two other TSs, P/CAF and SRC1. We set out to establish whether the intrinsic AT activity of CBP contributes to transcriptional activation. We show that a region of CBP, encompassing the previously defined histone AT (HAT) domain, can stimulate transcription when tethered to a promoter. The stimulatory effect of this activation domain shows some promoter preference and is dependent on AT activity. Analysis of 14 point mutations reveals a direct correlation between CBP's ability to acetylate histones in vitro and to activate transcription in vivo. We also find that the HAT domains of CBP and P/CAF share sequence similarity. Four conserved motifs are identified, three of which are analogous to motifs A, B and D, found in other N-acetyltransferases. The fourth motif, termed E, is unique to CBP and P/CAF. Mutagenesis shows that all four motifs in CBP contribute to its HAT activity in vitro and its ability to activate transcription in vivo. These results demonstrate that the AT activity of CBP is directly involved in stimulating gene transcription. The identification of specific HAT domain motifs, conserved between CBP and P/CAF, should facilitate the identification of other members of this AT family.
The T-cell receptor (TCR) -chain promoters have been characterized as nonstructured basal promoters that carry a single conserved ubiquitous cyclic AMP-responsive element. Our investigation of the human TCR  gene uncovers a surprisingly complex and tissue-specific structure at the TCR V 8.1 promoter. The core of the promoter (positions ؊42 to ؉11) is recognized by the lymphoid cell-specific transcription factors Ets-1, LEF1, and AML1 as well as by CREB/ATF-1, as is demonstrated in gel shift and footprinting experiments. With the exception of LEF1, these factors activate transcription in T cells. Binding sites at the core region show little conservation with consensus sites. Nonetheless, CREB, Ets-1, and AML1 bind and activate cooperatively and very efficiently through the nonconsensus binding sites at the core promoter region. Moderate ubiquitous activation is further induced by CREB/ATF and Sp1 factors through proximal upstream elements. The tissue-specific core promoter structure is apparently conserved in other T-cell-specifically expressed genes such as the CD4 gene. Our observations suggest that both the enhancer and the promoter have a complex tissue-specific structure whose functional interplay potentiates T-cell-specific transcription.T-cell-specific expression of the T-cell receptor (TCR)-CD3 complex and the CD4-CD8 coreceptors depends on distal enhancer elements (8,18,22,29,31,38,46,64,78,80), which is reminiscent of the B-cell-specific regulation of transcription of the immunoglobulin genes (4). The enhancers contain multiple binding sites for ubiquitous, lymphoid cell-and T-cell-specific factors (reviewed in references 9 and 40). Many T-cell-and lymphoid cell-specific factors were initially identified because they bind to functional important elements of the TCR enhancers. Examples are members of the family of high-mobilitygroup (HMG) box-containing factors TCF1 and LEF1 (T-cell factor 1 and lymphoid enhancer binding factor 1) (74,75,77), the zinc finger protein Ikaros (17,49), and the runt domain factor PEBP2␣ (polyomavirus enhancer binding protein 2␣). The latter, also called CBF␣ (core binding factor ␣), is the murine homolog of human AML1 (52), which is involved in the induction of acute myeloid leukemia (reviewed in references 30 and 50). In addition, the lymphoid cell-specific factors Ets-1, Elf-1, and GATA3 as well as the ubiquitous CREB/ATF family bind to and activate the TCR enhancers (16,20,28,43,79,80).Expression of the TCR genes is dependent on distal enhancers (22,38,40,46). Like other tissue-specific and inducible enhancer elements (for reviews, see references 72 and 73), the TCR enhancers assemble the transcription factors in a complex multiprotein structure (19,20). The corresponding promoters are thought to contribute little to tissue-specific transcription of TCR genes (40). For example, sequence comparisons of the different -chain promoters revealed only one conserved element (1, 59, 69). It resembles a cyclic AMPresponsive element (CRE) and is recognized by different members o...
The CREB-CREM transcription factors are the main gene regulatory effectors of the cAMP signaling pathway. The investigations of this family of transcription factors had a profound impact on the understanding of signaling-induced gene transcription. Here we discuss some key aspects of the underlying biology, review transcriptional activation by CREB proteins through transcription cofactors and present novel insights into the context- and position-specific function of CREB on complex genes.
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