Elsevier

Biochemical Pharmacology

Volume 68, Issue 6, 15 September 2004, Pages 1145-1155
Biochemical Pharmacology

CBP and p300: HATs for different occasions

https://doi.org/10.1016/j.bcp.2004.03.045Get rights and content

Abstract

The transcriptional coactivators CREB binding protein (CBP) and p300 are key regulators of RNA polymerase II-mediated transcription. Genetic alterations in the genes encoding these regulatory proteins and their functional inactivation have been linked to human disease. Findings in patients, knockout mice and cell-based studies indicate that the ability of these multidomain proteins to acetylate histones and other proteins is critical for many biological processes. Furthermore, despite their high degree of homology, accumulating evidence indicates that CBP and p300 are not completely redundant but also have unique roles in vivo. Recent studies suggest that these functional differences could be due to differential association with other proteins or differences in substrate specificity between these acetyltransferases. Inactivation of the acetyltransferase function of either CBP or p300 in various experimental systems will no doubt teach us more about the specific biological roles of these proteins. Given the wide range of human diseases in which CBP and/or p300 have been implicated, understanding the mechanisms that regulate their activity in vivo could help to develop novel approaches for the development of therapeutic strategies.

Section snippets

Chromatin and acetylation

Regulation of transcription is a central mechanism by which cells respond to developmental and environmental cues. RNA polymerase II-mediated transcription in eukaryotes is to a large extent regulated at the level of chromatin, which forms a physical barrier for the binding of proteins to the promoter region of a target gene. The basic unit of chromatin is the nucleosome, which consists of an octamer of histone proteins around which the DNA is wrapped (see Fig. 1). The nucleosomes form an array

Structure and function of the CBP and p300 proteins

The family of mammalian HATs includes CBP and its paralogue p300. CBP and/or p300 homologues are present in many multicellular organisms, including flies, worms and plants, but not in lower eukaryotes such as yeast [16], [17], [18]. CBP and p300 are ubiquitously expressed during mouse development [19]. Comparison of the amino acid sequences of these multidomain proteins from different species revealed the presence of numerous regions of near identity, including three cysteine–histidine rich

CBP, p300 and human disease

The importance of CBP and p300 is underscored by the fact that genetic alterations in their genes and functional inactivation of the proteins are strongly linked to human disease [70], [71], [72], [73]. De novo chromosomal translocations, microdeletions and point mutations in one copy of the CBP gene result in a congenital developmental disorder named RTS, which is characterised by retarded growth and mental function, broad thumbs, broad big toes and typical facial abnormalities [74].

Regulation of CBP and p300 acetyltransferase activity

The importance of the acetyltransferase function of CBP and p300 in fundamental biological processes indicates that this enzymatic activity is likely to be subject to regulation. The HAT activity of CBP and p300 is upregulated through phosphorylation by p42/p44 MAP kinase [29], cdk2 [28] or protein kinase A (PKA [111]). Conversely, protein kinase Cδ-mediated phosphorylation of a conserved serine residue at position 89 (S89) reduces the acetyltransferase activity of CBP [112]. It should be noted

Functional similarities and differences

The high degree of homology between CBP and p300 suggests that these proteins could, at least in part, be functionally redundant. While CBP was originally isolated as a coactivator of the transcription factor CREB [116], and p300 was cloned as a protein interacting with the transforming adenoviral E1A protein [117], both proteins were subsequently shown be interchangeable for these functions [118], [119]. The realization that CBP and p300 function as coactivators not only for CREB, but also for

Concluding remarks

The transcriptional coactivators CBP and p300 have been implicated in a plethora of transcriptional events, often based on overexpression of these proteins. However, inactivation of their genes in humans (RTS), mice or tissue culture cells indicate that their mode of action is far more specific than suggested by these overexpression studies. Furthermore, these studies also show that these proteins have common as well as unique functions, with the HAT/FAT function being critical in many cases.

Acknowledgements

Thanks to Olivier van Beekum, Leo Klomp, Paul Coffer (Pulmonary diseases, UMC, Utrecht) and David A. Baker (Molecular Cell Biology, LUMC, Leiden) for critically reading the manuscript. The author is supported by a fellowship from the Royal Netherlands Academy of Arts and Sciences.

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