Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition

Abstract

In eukaryotic cells, gene transcription is regulated by sequence-specific DNA-binding transcription factors that recognize promoter and enhancer elements near the transcriptional start site. Some coactivators promote transcription by connecting transcription factors to the basal transcriptional machinery. The highly conserved coactivators CREB-binding protein (CBP) and its paralog, E1A-binding protein (p300), each have four separate transactivation domains (TADs) that interact with the TADs of a number of DNA-binding transcription activators as well as general transcription factors (GTFs), thus mediating recruitment of basal transcription machinery to the promoter. Most promoters comprise multiple activator-binding sites, and many activators contain tandem TADs, thus multivalent interactions may stabilize CBP/p300 at the promoter, and intrinsically disordered regions in CBP/p300 and many activators may confer adaptability to these multivalent complexes. CBP/p300 contains a catalytic histone acetyltransferase (HAT) domain, which remodels chromatin to 'relax' its superstructure and enables transcription of proximal genes. The HAT activity of CBP/p300 also acetylates some transcription factors (e.g., p53), hence modulating the function of key transcriptional regulators. Through these numerous interactions, CBP/p300 has been implicated in complex physiological and pathological processes, and, in response to different signals, can drive cells towards proliferation or apoptosis. Dysregulation of the transcriptional and epigenetic functions of CBP/p300 is associated with leukemia and other types of cancer, thus it has been recognized as a potential anti-cancer drug target. In this review, we focus on recent exciting findings in the structural mechanisms of CBP/p300 involving multivalent and dynamic interactions with binding partners, which may pave new avenues for anti-cancer drug development.

Molecular cloning and functional characterization of cyclin E and CDK2 from Penaeus monodon

“…Phosphorylation of Smad3 suppresses its transcriptional activity and eventually accelerates cell cycle progression (Zieba et al, 2012). Moreover, phosphorylation of CBP/p300 and E2F-5 by cyclin E/CDK2 can activate transcriptional events as the cell cycle progresses (Wang et al, 2013;Chen et al, 2014). Despite the important role played by cyclin E/CDK2 in the cell cycle, the functional characterization of this complex has predominately been focused on vertebrate species, particularly mammals (Sheaff et al, 1997;Kolupaeva and Basilico, 2012;Duong et al, 2013).…”

C646, a Novel p300/CREB-Binding Protein-Specific Inhibitor of Histone Acetyltransferase, Attenuates Influenza A Virus Infection

“…The transcriptional coactivators p300 and CREB-binding protein (CBP) are important members of HAT families possessing HAT activity to influence chromatin activity. p300/CBP HATs are associated with tumorigenesis (14) and the development of many viral diseases (15)(16)(17)(18). Several small molecules have been shown to possess p300/CBP HAT inhibitory activity (19)(20)(21) and anti-influenza virus properties (22)(23)(24).…”

Forkhead followed by disordered tail: The intrinsically disordered regions of FOXO3a

“…109,110 CBP/p300 serves as a transcriptional coactivator for many important transcription factors, including p53, 111 E2A, 112 and FOXO3a, 48,110 and also acts as a histone acetyltransferase to remodel chromatin thereby rendering genes accessible for transcription. The interaction between CBP/p300 and FOXO3a is promiscuous and multi-valent, involving several domains and regions on both proteins.…”