npg CBP/p300 and lung cancer 324 Cell Research (2007) 17: 324-332 npg © 2007 IBCB, SIBS, CAS All rights reserved 1001-0602/07 $ 30.00 REVIEW www.nature.com/cr Roles of CREB-binding protein (CBP)/p300 in respiratory epithelium tumorigenesis Michalis V Karamouzis1, Panagiotis A Konstantinopoulos1, 2, Athanasios G Papavassiliou1 1Department of Biological Chemistry, Medical School, University of Athens, 75, M Asias Street, 11527 Athens, Greece; 2Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA CREB-binding protein (CBP) and its homologue p300 are transcriptional co-activators of various sequence-specific transcription factors that are involved in a wide array of cellular activities, such as DNA repair, cell growth, differentia- tion and apoptosis. Several studies have suggested that CBP and p300 might be considered as tumour suppressors, with their prominent role being the cross-coupling of distinct gene expression patterns in response to various stimuli. They exert their actions mainly via acetylation of histones and other regulatory proteins (e.g. p53). A major paradox in CBP/ p300 function is that they seem capable of contributing to various opposed cellular processes. Respiratory epithelium tumorigenesis represents a complex process of multi-step accumulations of a gamut of genetic and epigenetic aberra- tions. Transcription modulation through the alternate formation of activating and repressive complexes is the ultimate converging point of these derangements, and CBP/p300 represents key participants in this interplay. Thus, illumination of their molecular actions and interactions could reveal new potential targets for pharmacological interventions in re- spiratory epithelium carcinogenesis. Keywords: CBP, p300, lung cancer, acetylation, transcription factor Cell Research (2007) 17:324-332. doi: 10.1038/cr.2007.10; published online 20 March 2007 Introduction fects, albeit abnormal heart formation was noted only in p300–/– mice, thus suggesting that both proteins are cAMP response element-binding protein-binding pro- necessary during embryogenesis with overlapping and tein (CBP) and p300 were originally identified as factors unique functions [6]. Consistently, double heterozygous binding to the cAMP response element-binding protein CBP+/– and p300+/– knockout mice are also embryonic (CREB) and the adenoviral E1A, respectively [1, 2]. The lethal. However, only CBP+/– mice display features of human CBP locus resides in the chromosomal region Rubinstein-Taybi syndrome (RTS) [6, 7], while a more 16p13.3 and shows homology to 22q13, where p300 is severe and penetrant RTS-like phenotype was found in located [3]. CBP/p300 proteins share several conserved mice in which one CBP allele was modified to express a regions, which constitute most of their known functional truncated CBP protein [7]. domains (Figure 1). CBP and p300 have interchangeable Apart from other structurally defined regions, CBP/p300 roles during embryonic development and in many processes have specific areas for interaction with a wide array of tran- govern cellular homeostasis [4, 5]. However, genetic and scription factors and co-factors (Figure 1). The plethora of molecular evidence suggests that they also fulfil distinct these interacting proteins indicates the unique involvement functions [3]. Homozygous CBP–/– and p300–/– knock- of CBP/p300 in transcriptional control as ubiquitous and out mice were inviable due to severe developmental de- versatile co-integrators. Many of the protein interactions with CBP/p300 are regulated by upstream signals. For ex- ample, phosphorylation of the transcription factor CREB Correspondence: Athanasios G Papavassiliou modulates its interaction with CBP, while hormones can Tel: +30-210-7462509; Fax: +30-210-7791207 induce the binding of CBP/p300 to nuclear receptors [8]. E-mail: [email protected] Notably, in some cases CBP/p300 can stimulate diverse Cell Research | www.cell-research.com Michalis V Karamouzis et al. npg 325 Transactivation Acetyltransferase Transactivation COOH NH2 66% 93% 86% 86% 66% 82% CBP 2441 a.a. BD QP KIX SID RID CH1 CH2 CH3 p300 2414 a.a. BD QP SID KIX RID CH1 CH2 CH3 Nuclear RXR CREB Elk-1 c-Fos SRC-1 receptors STAT2 c-Jun MyoD MyoD p53 HIF-1 Elk-1 E2F ACTR Ets-1 c-Myb GATA-1 Smad Mdm2 BRCA1 E1A p53 SREBP p53 Tax p73 p53 pCAF STAT1 SV40 large T pp90 RSK E1A p73 TBP TBP c-Jun Figure 1 Schematic representation of CBP and p300 homologous regions and functional domains along with a selected list of proteins that bind to specific sites of CBP/p300. BD, bromodomain; CH1-3, cysteine and histidine-rich regions 1-3; KIX, binding site of CREB; QP, glutamine- and proline-rich domain; RID, receptor-interacting domain; SID, steroid receptor co-activator-1 interaction domain. functions of certain transcriptional regulatory proteins [4, CBP/p300 transcriptional activity 5]. Nevertheless, the most intriguing feature of CBP/p300 is their stoichiometric function in vivo and their intrinsic The multifaceted role of CBP/p300 in transcription can enzymatic activities. be achieved by various mechanisms (Figure 2). CBP/p300 The importance of CBP/p300 is underscored by the are thought to serve as a physical “bridge” between diverse fact that genetic alterations as well as their functional dys- gene-specific transcription factors (GSTFs) and compo- regulation are strongly linked to human diseases. Germline nents of the basal transcriptional machinery (BTM; e.g. mutations of CBP were first reported in RTS, an autosomal- TATA box-binding protein, TFIIB, TFIIE, TFIIF) thereby dominant disease characterised by mental retardation, skel- stabilising the transcription complex [4]. CBP/p300 might etal abnormalities and a high malignancy risk, albeit such also act as a scaffold for the formation of multi-component defects have not been associated with p300 so far [9, 10]. complexes containing transcription factors and co-factors. Nonetheless, mutations of the p300 gene have been detected A classical example of complex assembly involving mul- in human epithelial tumours, which is consistent with the tiple transcription factors and co-factors is the β-interferon general notion that p300 might possess tumour-suppressor gene promoter in response to viral infections [14]. The activity [11, 12]. Although the tumour-suppressor function large size of CBP/p300 endows them with many different of CBP is still unclear, its involvement in chromosomal interaction surfaces, thus enabling them to bind concur- translocations associated with haematologic malignancies rently to various proteins. By providing a platform for the has been well-documented [13]. The critical involvement of assembly of transcription regulatory proteins, CBP/p300 CBP/p300 proteins in a variety of key molecular pathways might increase the relative concentration of these factors provides the mechanistic rationale of their implication in in the local transcriptional environment (Figure 2). Ac- respiratory epithelium tumorigenesis. cordingly, cells can cooperatively utilise its repertoire www.cell-research.com | Cell Research npg CBP/p300 and lung cancer 326 CBP/p300 GSTF BTM DNA Other 1 co-factors Post-translational CBP/p300 modifications 2 GSTF GSTF GSTF CBP/p300 DNA Auto- acetylation GSTF Ac Histone 3 acetylation CBP/p300 acetylation Ac Ac Ac Ac Ac Ac GSTF BTM DNA Ac Ac Ac Ac Nucleosome Figure 2 CBP/p300 participate in transcriptional control through various mechanisms. (1) “Bridging” GSTFs with the BTM. (2) Contributing to the formation of multi-protein complexes and directly and/or indirectly modulating the activation status of GSTFs through post-translational modifications. (3) Exhibiting acetyl-transferase activity on nucleosomes and certain GSTFs. Ac, acetyl group. of proteins, so that the combinations of a few ubiquitous to enhance DNA-binding activity and gene transcription factors, and signal- and tissue-specific modulators, could [24]. Moreover, CBP/p300 can bind additional co-factors create a broad spectrum of regulatory complexes. that possess acetyl-transferase activity (e.g. p300/CBP- Post-translational chromatin modifications modulate the associated factor (p/CAF)) [25], and also recruit proteins activity of many genes by modifying both the core histones bearing other chromatin-modifying enzymatic activities and non-histone transcription factors [15]. Acetylation of (e.g. histone methyltransferases) [26]. multiple sites in the histone tails has been directly associ- The ability of so many proteins to interact with CBP/p300 ated with transcriptional upregulation, while de-acetylation suggests that competition for the rather limited intracellular correlates with transcriptional repression. Mechanistically, pool of CBP/p300 might account for the observation that histone acetylation promotes the accessibility of DNA to unrelated transcription factors inhibit each other without transcription protein complexes, by facilitating the “unwir- direct interference [27, 28]. In this vein, sequestration of ing” of the chromatin structure [16]. CBP/p300 can interact CBP/p300 by the adenoviral protein E1A [29], human with chromatin nucleosomes via nucleosome assembly papilloma virus protein E6 [30] and other viral proteins proteins, histone-binding proteins and possibly histones [3] is probably a means by which oncogenic viruses sup- themselves [17, 18]. In addition to histones, CBP/p300 also press many cellular transcription factors, and thereby may modulate a variety of other proteins by acetylation [19, 20].