A Large Number of Nuclear Receptor Coregulators Also Participate in Regulating Transcription
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p521-522
2025-12-06
77
Chromatin remodeling (histone modifications, DNA methylation, nucleosome repositioning/remodeling/displacement) transcription factor modification by various enzyme activities, and the communication between the nuclear receptors and the basal transcription apparatus are accomplished by protein-protein interactions with one or more of a class of coregulator molecules. The number of these coregulator molecules now exceeds 100, not counting species variations and splice variants. The first of these to be described was the CREB-binding protein, CBP. CBP, through an amino-terminal domain, binds to phosphorylated serine 137 of CREB and mediates transactivation in response to cAMP. It thus is described as a coactivator. CBP and its close relative, p300, interact directly or indirectly with a number of DNA-binding transcription factors, including activator protein-1 (AP-1), STATs, nuclear receptors, and CREB (Figure 1). CBP/p300 also binds to the p160 family of coactivators described later and to a number of other proteins, including the p90rsk protein kinase and RNA helicase A. It is important to note, as mentioned earlier, that CBP/p300 also has intrinsic histone acetyltransferase (HAT) activity. Some of the many actions of CBP/p300, which appear to depend on intrinsic enzyme activities and its ability to serve as a scaffold for the binding of other proteins. Other coregulators serve simi lar functions.
Fig1. Several signal transduction pathways converge on CBP/p300. Many ligands that associate with membrane or nuclear receptors eventually converge on CBP/p300. Several different signal transduction pathways are illustrated. (EGF, epidermal growth factor; GH, growth hormone; Prl, prolactin; TNF, tumor necrosis factor; other abbreviations are expanded in the text.)
Several other families of coactivator molecules have been described. Members of the p160 family of coactivators, all of about 160 kDa, include (1) SRC-1 and NCoA-1; (2) GRIP 1, TIF2, and NCoA-2; and (3) p/CIP, ACTR, AIB1, RAC3, and TRAM-1 (Table 1). The different names for members within a subfamily often represent species variations or minor splice variants. There is about 35% amino acid identity between members of the different subfamilies. The p160 coactivators share several properties. They (1) bind nuclear receptors in an agonist- and AF-2 AD-dependent manner, (2) have a con served amino terminal basic helix-loop-helix (bHLH) motif (see Chapter 38), (3) have a weak carboxyl-terminal transactivation domain and a stronger amino-terminal transactivation domain in a region that is required for CBP-p160 interaction, (4) contain at least three of the LXXLL motifs required for protein–protein interaction with other coactivators, and (5) often have HAT activity. The role of HAT is particularly interesting, as mutations of the HAT domain disable many of these transcription factors. Current thinking holds that these HAT activities acetylate histones, which facilitate the remodeling of chromatin into a transcription-efficient environment. Histone acetylation/deacetylation thus plays a critical role in gene expression. Finally, it is important to note that other protein substrates for HAT-mediated acetylation, such as DNA binding transcription activators and other coregulators have been reported. Such nonhistone PTM events likely also factor importantly into the overall regulatory response.
Table1. Some Mammalian Coregulator Proteins
A small number of proteins, including NCoR and SMRT, comprise the corepressor family. They function, at least in part. Another family includes the TRAPs, DRIPs, and ARC (see Table 1). These proteins rep resent subunits of the mediator and range in size from 80 to 240 kDa and are thought to link the nuclear receptor-coactivator complex to RNA polymerase II and the other components of the basal transcription apparatus.
The exact role of these coactivators is presently under intensive investigation. Many of these proteins have intrinsic enzymatic activities. This is particularly interesting in view of the fact that acetylation, phosphorylation, methylation, sumoylation, and ubiquitination—as well as proteolysis and cellular translocation—have been proposed to alter the activity of some of these coregulators and their targets.
It appears that certain combinations of coregulators—and thus different combinations of activators and inhibitors—are responsible for specific ligand-induced actions through various receptors. Furthermore, these interactions on a given promoter are dynamic. In some cases, complexes consisting of over 45 transcription factors have been observed on a single gene.
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