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Journal of Cellular Biochemistry 96:1127–1136 (2005) The Fellowships of the INGs Xiaobing Shi and Or Gozani* Department of Biological Sciences, Stanford University, Stanford, California 94305-5020 Abstract The inhibitor of growth (ING) family of proteins is an evolutionarily conserved family, with members present from yeast to humans. The mammalian ING proteins are candidate tumor suppressor proteins and accordingly can cooperate with p53 to arrest proliferation and induce apoptosis. ING proteins are also reported to function in the promotion of cellular senescence, the regulation of DNA damage responses and the inhibition of angiogenesis. At the molecular level, ING proteins are thought to function as chromatin regulatory molecules, acting as co-factors for distinct histone and factor acetyl-transferase (H/FAT) and deacetylase (HDAC) enzyme complexes. Further, ING proteins interact with a number of additional proteins involved in the regulation of critical nuclear processes, such as gene expression and DNA replication, and also function as nuclear phosphoinositide (PtdInsP) receptors. Despite the increasing number of known molecular interacting partners for ING proteins, the specific biochemical action of mammalian ING proteins and its relationship to tumor suppression remain elusive. In this Prospect, we summarize the present understanding of the binding partners and physiologic roles of ING proteins and propose a general molecular paradigm for how ING proteins might function to prevent cancer. J. Cell. Biochem. 96: 1127–1136, 2005. ß 2005 Wiley-Liss, Inc. Key words: ING1; ING2; PHD finger; phosphoinositide; chromatin modification ING family members are present throughout tion, promotion of apoptosis and cellular senes- eukaryotic proteomes [He et al., 2005]. The best- cence, contact inhibition, DNA damage repair, characterized members include the five human and inhibition of angiogenesis (for review see members (INGs1-5) and three S. cerevisiae [Nouman et al., 2003; Campos et al., 2004; Gong members(Yng1,Yng2,andPho23.)Thefounding etal.,2005;Kim,2005]andreferencestherein).In member of the family, ING1, was identified using this context, multiple tumors have been found to an approach designed for discovery of genes either (i) harbor mutations within ING genes, (ii) whose expression was suppressed in cancer cells have reduced expression of ING proteins, or (iii) [Garkavtsev et al., 1996]. Accordingly, ING1 was have altered ING protein sub-cellular localiza- subsequently shown to cooperate with p53 to tion. Based on these collective findings, mamma- induce apoptosis and cellular senescence, activ- lian INGs are now thought to function as type II ities consistent with the notion that ING1 is a tumor suppressors (reviewed in [Gong et al., tumor suppressor [Garkavtsev and Riabowol, 2005]). 1997; Garkavtsev et al., 1998]. Since the dis- Studies in both yeast and human cells suggest covery of ING1, studies from multiple groups that ING proteins exert their biological functions have implicated ING1 as well as other family through their associations with specific molecu- members in negative regulation of cell prolifera- lar partners. For the purpose of this Prospect, we divide these interacting partners of ING proteins into three groups: (i) components of HAT or HDAC complexes, (ii) other proteins involved in nuclear regulatory functions (e.g., p53 and NF- kB), and (iii) the signaling lipids, PtdInsPs. Grant sponsor: Burroughs Wellcome Fund and NIH; Grant Below we review these interactions and discuss number: KO8 AG19245. the possibility that ING proteins function by *Correspondence to: Or Gozani, Department of Biological Sciences, 371 Serra Mall Drive, Building Gilbert, Room integrating stress-induced PtdInsP signaling to 208A, Stanford University, Stanford, CA 94305-5020. (i) facilitate the assembly and (ii) regulate the E-mail: [email protected] sub-nuclear localization of distinct complexes Received 28 July 2005; Accepted 29 July 2005 consisting of different combinations of group (i) DOI 10.1002/jcb.20625 and (ii) interactors. ß 2005 Wiley-Liss, Inc. 1128 Shi and Gozani STRUCTURE AND FUNCTION OF ING are direct or mediated by co-associated proteins; PROTEIN DOMAINS ING1 has been reported to bind directly to p53 [Leung et al., 2002]. However, we have not All of the ING proteins share a relatively detected direct interactions between ING2 and similar architecture, containing an N-terminal p53 in vitro (O. Gozani, unpublished observa- protein–protein interaction region, a centrally tions), though the interaction might depend on located nuclear localization signal (NLS) and a either ING2 or p53 having undergone a specific C-terminal plant homeodomain (PHD) finger post-translational modification in vivo. Regard- module. The N-termini of ING proteins mediate less, there is clear evidence that ING proteins the majority of reported protein–protein inter- and p53 are in a common signaling pathway and actions, with two functionally defined domains, almost certainly share common protein binding- named the PCNA-interacting protein (PIP) and partners. In this regard, multiple groups have SAP30 interacting domain (SAID) domains found that ING protein-induced apoptosis [Scott et al., 2001; Kuzmichev et al., 2002]. requires p53 and that p53-induced apoptosis is The PIP domain mediates a direct interaction potentiated by co-expression of INGs. Further, with PCNA. This interaction is specifically indu- the ability of ectopically expressed p53 to ced upon UV damage and is hypothesized to transactivate a reporter plamsid in S. cerevisiae switch PCNA activity away from DNA replica- requires Yng2 [Nourani et al., 2001]. Notably, tion towards DNA repair [Scott et al., 2001]. this activity of Yng2 is dependent on the Interestingly, in yeast, Yng2 mutants are presence of the Yng2 PHD finger, but is not synthetically lethal with DNA replication due to a direct interaction between Yng2 and mutants, suggesting that regulation of replica- p53 (discussed below) [Nourani et al., 2001]. tion-coupled repair might be evolutionarily Recently, ING4 was shown to physically conserved [Choy and Kron, 2002]. interact with nuclear factor-kB (NF-kB) and To date, it appears that among ING members, repress its transcriptional activity [Garkavtsev the PIP domain is unique to ING1. In contrast, et al., 2004]. Interestingly, ING4 truncations the SAID domain, which was defined as the augmented NF-kB activity, presumably via region of ING1 that directly interacts with the dominant-negative effects. This dominant nega- Sin3a associated protein sin3-associated pro- tive activity might indicate sequestration by tein 30 (SAP30), is likely also present on ING2 this domain of ING4 interacting proteins (or and PHO23, since both of these proteins directly ING4 itself) that are normally involved in interact with SAP30 ([Loewith et al., 2001; inhibiting NF-kB [Garkavtsev et al., 2004]. In Kuzmichev et al., 2002]; O. Gozani, unpublished this regard, reversible acetylation of NF-kBis observations). This interaction is thought to thought to regulate its transcriptional activa- bridge ING1, ING2, and Pho23 to SAP30- tion, DNA binding affinity, I-kBa association containing HDAC1/2 complexes. and subcellular localization (reviewed in All of the human ING proteins (with the [Greene and Chen, 2004]). ING4 has been exception of an alternatively spliced isoform of reported to interact, when overexpressed, with ING1 (ING1a)) have been shown in overexpres- the HAT p300, and is likely to be a component of sion studies to promote the transactivity of the this HAT or possibly another HAT/HDAC tumor suppressor p53 [Nagashima et al., 2001, complex [Shiseki et al., 2003]. Thus, ING4 2003; Vieyra et al., 2002b; Shiseki et al., 2003]. might inhibit NF-kB activity via regulation of It is proposed that ING proteins facilitate p53- acetylation. Further, since p53 and NF-kB are dependent transcription through one of several generally thought to have antagonistic func- mechanisms, including: (i) opening of chroma- tions, potential connections between ING4-p53 tin at p53-target promoters by recruitment of interactions and ING4-NF-kb interactions ING-containing HAT/HDAC enzymes via ING- might exist, though presently such connections p53 interactions, (ii) facilitation of p53 acetyla- have not been explored. tion by ING proteins, likely mediated by ING- p53 interactions and subsequent acetylation by THE PHD FINGER AS A SIGNALING MODULE ING-associated HATs, and (iii) inhibition of the p53 deacetylase SIRT1 [Feng et al., 2002; Cheng The greatest homology among the ING pro- et al., 2003; Kataoka et al., 2003]. Presently, it teins occurs within the highly conserved PHD remains unclear whether ING-p53 interactions zinc finger motif [He et al., 2005]. This module is Role of ING Proteins in Nuclear Signaling 1129 found throughout eukaryotic proteomes, pre- Insight into the biologic function of PHD dominantly on chromatin-associated proteins fingers comes in part from studies of the struc- [Sutherland et al., 2001]. Structurally, the PHD turally related FYVE and RING finger modules finger belongs to the treble class of zinc-binding [Pascual et al., 2000; Capili et al., 2001]. The domains, containing two zinc ions bound in a FYVE finger is a well-characterized PtdInsP- cross-braced topology [Pascual et al., 2000]. binding module, and RING fingers function as Zinc-coordination by PHD fingers is achieved components of E3 ubiquitin ligase enzymes via ligation of zinc atoms to alternating pairs of (reviewed in [Misra et al., 2001; Stenmark