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CBP/P300 in Cell Growth, Transformation, and Development

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CBP/P300 in Cell Growth, Transformation, and Development Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW CBP/p300 in cell growth, transformation, and development Richard H. Goodman1,3 and Sarah Smolik2 1Vollum Institute and 2Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201 USA CREB binding protein (CBP) and p300 were both identi- of hematological malignancies, including histiocytic sar- fied initially in protein interaction assays–the former comas, monomyelocytic leukemia, and lymphocytic through its association with the transcription factor leukemia. More aggressive forms of leukemia developed CREB (Chrivia et al. 1993) and the latter through its in- in sublethally irradiated recipients transplanted with teraction with the adenoviral-transforming protein E1A bone marrow or splenocytes from the CBP heterozy- (Stein et al. 1990; Eckner et al. 1994). The recognition gotes. Overall, nearly 40% of the CBP heterozygotes ei- that these two proteins, one involved in transcription ther developed tumors or harbored tumorigenic cells and the other in cell transformation, had highly con- that were revealed by the transplantation assay. Analysis served sequences suggested that they had the potential of tumors isolated from the irradiated recipients revealed to participate in a variety of cellular functions (Fig. 1). that the wild-type CBP allele was typically lost as well. Several excellent reviews (Janknecht and Hunter 1996; This loss of heterozygosity in a population of cells that Shikama et al. 1997; Giles et al. 1998) have addressed the undergoes transformation is a hallmark feature of a tu- transcriptional coactivator functions of CBP/p300; this mor-suppressor gene. As discussed below, human pa- review focuses on the involvement of these proteins in tients with the Rubinstein-Taybi syndrome (RTS), due to the complex biological processes that affect cell growth, CBP heterozygosity, also have an increased incidence of transformation, and development. malignancy. Surprisingly, the hematological defects and cancer predisposition were not seen in mice that con- tained the identical mutation in one p300 allele. How- Involvement of CBP/p300 in cell growth ever, a tumor-suppressor role for p300 in humans is not and transformation inconceivable. Muroaka et al. (1996) identified p300 mis- sense mutations associated with loss of heterozygosity CBP/p300 as tumor suppressors in tumors from two patients, one with colorectal and the One of the major paradoxes in CBP/p300 function is that other with gastric carcinoma, and Gayther et al. (2000) these proteins appear to be capable of contributing to recently reported five additional examples. diametrically opposed cellular processes. This section The growth suppression functions of CBP and p300 are begins with a review of the evidence that CBP and p300 also exemplified by their interactions with the tumor participate in various tumor-suppressor pathways. It suppressor p53. Most of the critical functions of p53 are ends with the demonstration that these coactivators are believed to occur through its ability to activate genes essential for the actions of many oncogenes. Whether involved in the response to DNA damage, such as mu- CBP and p300 promote apoptosis or cell proliferation ap- rine double minute (mdm-2), p21, cyclin G, and bax. pears to be highly context dependent. Studies have shown that p53 interacts with a carboxy- Several characteristics of CBP and p300 suggested that terminal region of CBP/p300 and that this interaction these proteins might serve as tumor suppressors, but contributes to transcriptional activation of the p53-re- clear evidence for this function awaited the studies of sponsive mdm-2, p21, and bax promoters (Avantaggiati Kung et al. (2000). Mice engineered to contain a null et al. 1997; Gu et al. 1997; Lill et al. 1997). Because ad- mutation in one CBP allele developed a variety of hema- enovirus E1A blocks CBP/p300 function (see below), it tological abnormalities, including extramedullary my- has been suggested that at least some of its effects on cell elopoiesis and erythropoiesis, lymph node hyperplasia, transformation might occur by inhibiting the actions of and splenomegaly. Most of these effects were attributed p53. Conversely, the growth suppression activities of to an underlying bone marrow failure. As the mutant CBP and p300 have been attributed to their ability to animals aged, they developed a strikingly high incidence augment p53-mediated transcription. In addition to its transcriptional activation functions, p53 negatively regulates genes whose promoters do not contain a suit- 3Corresponding author. able binding site. Avanaggiati et al. (1997) have suggested E-MAIL [email protected]; FAX (503) 494-4353. that the association of p53 and p300 might account for GENES & DEVELOPMENT 14:1553–1577 © 2000 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/00 $5.00; www.genesdev.org 1553 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Goodman and Smolik Figure 1. CBP/p300 organization and interactions. Interacting proteins are shown at the top of the figure; functional domains are depicted below. Many known interactions are not included due to space limitations. this effect, presumably by limiting access of the coacti- activation has been reviewed extensively (for example, vator to promoter-bound transcription factors such as see Strahl and Allis 2000). The studies of Gu and Roeder AP-1. p53 has also been shown to bind to the first zinc (1997) provided the first demonstration that acetylation finger region of CBP/p300 (Grossman et al. 1998; Wad- can regulate the transcriptional functions of non-histone gaonkar and Collins 1999), and this interaction has been proteins as well. Several additional transcriptional regu- proposed to participate in both p53 transcriptional acti- lators were shown subsequently shown to be modified vation and in targeting the tumor suppressor protein to- by acetylation, including EKLF, GATA-1, dTCF, NF-Y, ward a degradation pathway (see below). A p300-inter- TFIIE, TFIIF, HMGI(Y), c-myb, myo-D, HIV-1 Tat, and acting factor called JMY has been identified and proposed E2F (Imhof et al. 1997; Boyes et al. 1998; Li et al. 1998; to augment p53-dependent apoptosis (Shikama et al. Munshi et al. 1998; Waltzer and Bienz 1998; Zhang and 1999). Bieker 1998; Ott et al. 1999; Sartorelli et al. 1999; Mar- The finding by Gu and Roeder (1997) that p53 could be tinez-Balbas et al. 2000; Tomita et al. 2000). However, in acetylated by p300 uncovered a previously unrecognized most instances, precisely how acetylation affects the aspect of CBP/p300 function. Acetylation of specific ly- transcriptional properties of these other proteins is not sine residues in the carboxyl terminus of p53 was found completely understood. to increase DNA binding dramatically, presumably by CBP/p300 may also contribute to the mechanisms altering the conformation of an inhibitory regulatory do- that regulate p53 degradation. For example, the p53 pro- main. One model for how this might occur is that the tein is known to be stabilized in cells that express ad- neutralization of positively charged lysine residues enovirus E1A. As described above, E1A blocks the ability through acetylation might disrupt interactions between of p53 to induce its target genes, such as mdm2. Because the p53 carboxyl terminus and the core DNA-binding mdm2 is implicated in p53 degradation (Haupt et al. domain. The ability of p53 to be acetylated in vivo was 1997; Kubbutat et al. 1997), the block of mdm-2 expres- confirmed subsequently by using acetylation-specific an- sion by E1A would be expected to suppress a negative tibodies (Sakaguchi et al. 1998; Liu et al. 1999a). Lambert feedback loop (Wu et al. 1993), wherein the p53-medi- et al. (1998) have recently reported that ionizing irradia- ated induction of mdm-2 promotes p53 degradation. tion promotes the amino-terminal phosphorylation of Grossman et al. (1998) have shown that both p53 and p53, resulting in an increased affinity for CBP/p300 and mdm-2 bind to the first zinc finger domain of p300. an accompanying stimulation of p53 acetylation. mdm-2 mutants incapable of interacting with p300 (but Amino-terminal phosphorylation also decreases the af- still able to bind to p53) are defective for inducing p53 finity of p53 for mdm-2 (Chehab et al. 1999; Unger et al. degradation. Similarly, p53 mutants rendered incapable 1999), a protein that inhibits p53 function through a va- of interacting with p300 escape mdm-2-mediated degra- riety of mechanisms (for review, see Lozano and Oca dation. These findings led to the suggestion that inter- Luna 1998). action of mdm-2 and p53 with p300 is required for p53 The correlation between histone acetylation and gene turnover. One possible problem with this model is that 1554 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press CBP/p300 the degradation of p53 is believed to occur in a cytoplas- Chromosomal translocations mic compartment (Freedman and Levine 1998). How the nuclear p300 might assist mdm-2 in this cytoplasmic The participation of CBP/p300 in cell transformation is p53 degradation process is unclear. In contrast, Yuan et perhaps most evident from the study of various forms of al. (1999a) suggested that p300 might actually stabilize leukemia that are associated with CBP-disrupting chro- p53. Using cells engineered
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