MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation

Wang, Chuangui; Ivanov, Alexey V.; Chen, Lihong; Fredericks, William J.; Seto, Ed; Rauscher, Frank J.; Chen, Jiandong

doi:10.1038/sj.emboj.7600791

Cited by 231 publications

(228 citation statements)

References 44 publications

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“…Nuclei were pelleted, lysed in Triton X-100 buffer 46 and used for detection of transfected proteins by western blotting. Lentiviral vector-based KAP1 gene knockdown was performed as described previously 47 .…”

Section: Gene Repression Assaymentioning

confidence: 99%

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Zeng

Yap

Ivanov

et al. 2008

Nat Struct Mol Biol

118

117

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The tandem PHD finger-bromodomain, found in many chromatin-associated proteins, has an important role in gene silencing by the human co-repressor KRAB-associated protein 1 (KAP1). Here we report the three-dimensional solution structure of the tandem PHD finger-bromodomain of KAP1. The structure reveals a distinct scaffold unifying the two protein modules, in which the first helix, α Z , of an atypical bromodomain forms the central hydrophobic core that anchors the other three helices of the bromodomain on one side and the zinc binding PHD finger on the other. A comprehensive mutation-based structure-function analysis correlating transcriptional repression, ubiquitin-conjugating enzyme 9 (UBC9) binding and SUMOylation shows that the PHD finger and the bromodomain of KAP1 cooperate as one functional unit to facilitate lysine SUMOylation, which is required for KAP1 co-repressor activity in gene silencing. These results demonstrate a previously unknown unified function for the tandem PHD finger-bromodomain as an intramolecular small ubiquitin-like modifier (SUMO) E3 ligase for transcriptional silencing.Chemical modifications of chromatin on the DNA (for example, methylation of cytosine) and DNA-packing histones (for example, acetylation, methylation, phosphorylation, ubiquitination and SUMOylation) are important in the epigenetic control of gene transcription in response to physiological and environmental stimuli [1][2][3] . An emerging model suggests that there is an 'epigenetic code' embedded within chromatin to signify regions of distinct nuclear activities, such as heterochromatin formation or transcriptional activation [4][5][6] . It is thought that the epigenetic code is established by chromatin-modifying enzymes and interpreted by proteins that bind the chromatin in a modification-sensitive manner. The discovery of methyl-CpG binding domains 7 , bromodomains as acetyllysine binding The tandem bromodomain-PHD finger of the human transcriptional coactivator p300/CBP has been shown to be interdependent in interactions with nucleosomes 27 . A more common, reversely connected motif, the PHD finger-bromodomain, is found in many chromatinassociated proteins including histone lysine methyl-transferase MLL1 (ref. 28), Williams syndrome transcription factor (WSTF) in the chromatin-remodeling complex WINAC 29 , and the TIF1 family proteins (α, β, γ and δ; note that TIF1β is also known as KAP1 or TRIM28) 30 . This tandem PHD finger-bromodomain is also found in Sp140, a leukocytespecific protein in the nuclear body that is involved in the pathogenesis of acute promyelocytic leukemia and viral infection 31 . Mutations of PHD fingers, particularly those that disrupt zinc coordination, have been linked to tumor formation and genetic disorders 32 .More recently, it has been reported that the PHD finger of the human co-repressor KAP1 functions as a unique SUMO E3 ligase that is required for KAP1's gene transcription repression activity 33 .To understand its molecular function in gene silencing, we solved the three-dim...

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Section: Gene Repression Assaymentioning

confidence: 99%

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Zeng

Yap

Ivanov

et al. 2008

Nat Struct Mol Biol

118

117

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“…19 Fifth, MDM2 may also contribute to p53 inactivation by recruiting several corepressor proteins, such as HDAC1, 20 CTBP2, 21 YY1, 22 and KAP1. 23 A central negative regulator of MDM2 is the tumor suppressor protein p14 ARF , which is an alternate reading frame product of the CDKN2A locus on chromosome 9p21. This locus encodes two structurally unrelated growth-inhibitory proteins, p16 INK4a and p14 ARF , that govern the activities of the pRb and p53 tumor suppressor pathways, respectively.…”

mentioning

confidence: 99%

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

et al. 2009

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A primary failsafe program against unrestrained proliferation and oncogenesis is provided by the p53 tumor suppressor protein, inactivation of which is considered as a hallmark of cancer. Intriguingly, mutations of the TP53 gene are rarely encountered in neuroblastoma tumors, suggesting that alternative p53-inactivating lesions account for escape from p53 control in this childhood malignancy. Several recent studies have shed light on the mechanisms by which neuroblastoma cells circumvent the p53-driven antitumor barrier. We review here these mechanisms for evasion of p53-mediated growth control and conclude that deregulation of the p14 ARF -MDM2-p53 axis seems to be the principal mode of p53 inactivation in neuroblastoma, opening new perspectives for targeted therapeutic intervention. The p53 tumor surveillance network constitutes the core defense mechanism of the cell against loss of genomic integrity and malignant transformation. Evasion of p53 activity is, therefore, a prerequisite for tumor cells to survive and thrive, and this is attainable either through mutation of the TP53 gene or through defects in the molecular components that govern or execute the various aspects of the p53 response. Elucidation of the mechanisms by which tumor cells override the p53-orchestrated failsafe program is not only important to gain insight into the ontogenesis of a tumor, but may also point to preferable modes of therapeutic intervention.A striking feature of the childhood cancer neuroblastoma is the low frequency (o2%) of TP53 mutations at diagnosis. 1 There is considerable evidence that TP53 mutations may be acquired during chemotherapy and malignant progression of neuroblastoma. 1-4 Accordingly, an increased frequency of TP53 mutations is observed in multidrug-resistant neuroblastoma cell lines and in neuroblastoma cell lines established at relapse, but even in this context, the majority of cell lines remain characterized by a wild-type TP53 gene. 5,6 Furthermore, many studies indicate that the p53 signal transduction pathway is intrinsically intact in neuroblastoma, 1,4,7-9 suggesting that circumvention of the p53 barrier in this tumor entity relies primarily on an inappropriately increased activity of inhibitors of p53 signaling or, alternatively, on a loss of positive regulators of p53 activity. This review summarizes our current understanding of the mechanisms by which neuroblastoma cells escape from p53-mediated tumor surveillance and positions deregulation of the p14 ARF -MDM2-p53 axis as a central switch for p53 inactivation in neuroblastoma.The p14 ARF -MDM2-p53 Axis and Lesions at the MDM2 and CDKN2A (p16 INK4a /p14 ARF ) Loci in NeuroblastomaThe MDM2 oncoprotein, a human homolog of the 'mouse double minute 2' gene product that was originally identified in a spontaneously transformed mouse cell line with double minute chromosomes, 10 is a critical negative regulator of p53 stability and activity. It has been well established that p53 and MDM2 mutually control their cellular levels and form a tight autoregulatory...

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“…Furthermore, this enhancement relied on the interaction between the two proteins, since the MAGE-G1 L96A/L97A mutant lost the enhancement effect. In the case of MAGE-C2-TRIM28 complex, MAGE-C2 could not only induce the ubiquitin ligase activity of TRIM28 itself, but also enhance the ubiquitination of its substrate p53 by TRIM28 (Wang et al, 2005;Doyle et al, 2010). In addition, Yang et al (2007) also showed that type I MAGEs binding to TRIM28 suppressed p53-dependent apoptosis in cancer cells.…”

Section: Function and Mechanism Of Mage-ring Complexesmentioning

confidence: 94%

When MAGE meets RING: insights into biological functions of MAGE proteins

2011

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The melanoma antigen (MAGE) family proteins are well known as tumor-specific antigens and comprise more than 60 genes, which share a conserved MAGE homology domain (MHD). Type I MAGEs are highly expressed cancer antigens, and they play an important role in tumorigenesis and cancer cell survival. Recently, several MAGE proteins were identified to interact with RING domain proteins, including a sub-family of E3 ubiquitin ligases. The binding mode between MAGEs and RING proteins was investigated and one important structure of these MAGE-RING complexes was solved: the MAGE-G1-NSE1 complex. Structural and biochemical studies indicated that MAGE proteins could adjust the E3 ubiquitin ligase activity of its cognate RING partner both in vitro and in vivo. However, the underlying mechanism was not fully understood. Here, we review these exciting advances in the studies on MAGE family, suggest potential mechanisms by which MAGEs activate the E3 activity of their binding RING proteins and highlight the anticancer potential of this family proteins. KEYWORDS MAGE, cancer testis antigen, RING, ubiquitin ligase, TRIM28 OVERVIEW OF THE MAGE FAMILY PROTEINSThe cancer/testis antigens are types of proteins that appear to be only present in germline cells, trophoblasts and tumors (Simpson et al., 2005). It is also implicated that aberrant expression of germline genes in cancer cells might be one of the driving forces of tumorigenesis. The family of cancer/testis antigens has undergone expansion during the past years, and now consists of more than 100 genes, with new members still being identified (Scanlan et al., 2004;Doyle et al., 2010). Cancer/testis antigen genes are widely expressed in various types of tumors, such as melanoma, carcinoma of the bladder and liver (Barker and Salehi, 2002;Miranda, 2010). These immunogenic features have endowed them the potential as therapeutic cancer vaccines (Simpson et al., 2005). Typically, this family is divided into three sub-families: melanoma antigen (MAGE), G antigen (GAGE), and X chromosome antigen (XAGE) families. The majority of these genes exist as multigene families, and are often under similar transcriptional regulation, leading to their co-expression in some contexts (Scanlan et al., 2002).The first identified member of this family, MZ2-E, was discovered in a patient with melanoma who had cytotoxic T cell recognizing tumor cells (van der Bruggen et al., 1991;Simpson et al., 2005). This gene was later found to belong to a 12-hMAGE-A genes cluster, and thus known as MAGE-A1 (Chomez et al., 2001). Since then, the MAGE family has extensively increased and more than 60 genes have been identified in humans up to now. Based on their different expression patterns, the MAGE family genes are subdivided into two categories. The type I MAGE genes are located in clusters of the X chromosome, and consist of MAGE-A, -B, and -C groups, with their expression restricted to testis, trophoblast, and placenta (Barker and Salehi, 2002;Simpson et al., 2005). Unlike MAGE I genes, type II MAGE gene...

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MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation

Cited by 231 publications

References 44 publications

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14ARF-MDM2-p53 axis

When MAGE meets RING: insights into biological functions of MAGE proteins

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