Tripartite Motif Containing 28 (Trim28) Can Regulate Cell Proliferation by Bridging HDAC1/E2F Interactions

Chen, Lu; Chen, Dung-Tsa; Kurtyka, Courtney A.; Rawal, Bhupendra; Fulp, William J.; Haura, Eric B.; Cress, W. Douglas

doi:10.1074/jbc.m112.380865

Cited by 90 publications

(99 citation statements)

References 48 publications

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“…However, the role of KAP1 in tumorigenesis is still inconclusive and seems to be tissue specific, since KAP1 showed tumor-suppressive functions in early-stage lung cancer by inactivating oncogenic transcription factors (71)(72)(73). Furthermore, KAP1 was shown to play a role in the MDM2/p53/HDAC1 complex, thereby promoting deacetylation and MDM2-mediated degradation of p53 (70).…”

Section: Discussionmentioning

confidence: 99%

KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

Bürck

Mund

Berscheminski

et al. 2016

J Virol

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Once transported to the replication sites, human adenoviruses (HAdVs) need to ensure decondensation and transcriptional activation of their viral genomes to synthesize viral proteins and initiate steps to reprogram the host cell for viral replication. These early stages during adenoviral infection are poorly characterized but represent a decisive moment in the establishment of a productive infection. Here, we identify a novel host viral restriction factor, KAP1. This heterochromatin-associated transcription factor regulates the dynamic organization of the host chromatin structure via its ability to influence epigenetic marks and chromatin compaction. In response to DNA damage, KAP1 is phosphorylated and functionally inactive, resulting in chromatin relaxation. We discovered that KAP1 posttranslational modification is dramatically altered during HAdV infection to limit the antiviral capacity of this host restriction factor, which represents an essential step required for efficient viral replication. Conversely, we also observed during infection an HAdV-mediated decrease of KAP1 SUMO moieties, known to promote chromatin decondensation events. Based on our findings, we provide evidence that HAdV induces KAP1 deSUMOylation to minimize epigenetic gene silencing and to promote SUMO modification of E1B-55K by a so far unknown mechanism. IMPORTANCEHere we describe a novel cellular restriction factor for human adenovirus (HAdV) that sheds light on very early modulation processes in viral infection. We reported that chromatin formation and cellular SWI/SNF chromatin remodeling play key roles in HAdV transcriptional regulation. We observed that the cellular chromatin-associated factor and epigenetic reader SPOC1 represses HAdV infection and gene expression. Here, we illustrate the role of the SPOC1-interacting factor KAP1 during productive HAdV growth. KAP1 binds to the viral E1B-55K protein, promoting its SUMO modification, therefore illustrating a crucial step for efficient viral replication. Simultaneously, KAP1 posttranslational modification is dramatically altered during infection. We observed an HAdV-mediated decrease in KAP1 SUMOylation, known to promote chromatin decondensation events. These findings indicate that HAdV induces the loss of KAP1 SUMOylation to minimize epigenetic gene silencing and to promote the SUMO modification of E1B-55K by a so far unknown mechanism.

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Section: Discussionmentioning

confidence: 99%

KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

Bürck

Mund

Berscheminski

et al. 2016

J Virol

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“…However, opposite conclusions were also reported. KAP1 overexpression is associated with better overall survival in early-stage lung cancer [14] . Furthermore, a mouse model showed that Kap1-depletion in liver increases male-predominant hepatic adenoma [120] (Table 2).…”

Section: Clinical Relevance Focused On Cancer Biologymentioning

confidence: 99%

“…Consequently, KAP1 epigenetically regulates gene expression through multiple transcriptional co-repressor complexes. In addition to regulating KRABZFPs, the activity of transcription factors lacking KRAB domain, such as c-Myc and E2F1, can also be regulated by KAP1 [10][11][12][13][14] . KAP1 is subjected to multiple post-translational modifications (PTMs), including phosphorylation and SUMOylation ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

KAPtain in charge of multiple missions: Emerging roles of KAP1

Cheng

Kuo

Ann

2014

WJBC

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from conditional knockout mouse models reveal that KAP1-deficiency significantly impairs vital physiological processes, such as immune maturation, stress vulnerability, hepatic metabolism, gamete development and erythropoiesis. In this review, we summarize and evaluate current literatures involving the biochemical and physiological functions of KAP1. In addition, increasing studies on the clinical relevance of KAP1 in cancer will also be discussed. Key words: KRAB domain-associated protein 1; Transcriptional co-repressor; Post-translational modification; Chromatin remodeling; KRAB-containing zinc finger protein Core tip: This review article primarily summarizes the current findings of KAP1/TRIM28/TIF1β, with focuses on its biochemical and physiological functions. Both the canonical transcriptional co-repressor function and the transcriptional-independent roles of KAP1 are discussed in detail. We highlight the post-translational modifications and the compartmentalized localization of KAP1 and suggest that the function of KAP1 could be spatial and temporal regulated in multiple physiological circumstances. Finally, we summarize the clinical relevance of KAP1 in cancer and discuss the possibility to translate the mechanistic studies of KAP1 to human pathophysiology in the future. Abstract KAP1/TRIM28/TIF1β was identified nearly twenty years ago as a universal transcriptional co-repressor because it interacts with a large KRAB-containing zinc finger protein (KRAB-ZFP) transcription factor family. Many studies demonstrate that KAP1 affects gene expression by regulating the transcription of KRAB-ZFP-specific loci, trans-repressing as a transcriptional co-repressor or epigenetically modulating chromatin structure. Emerging evidence suggests that KAP1 also functions independent of gene regulation by serving as a SUMO/ubiquitin E3 ligase or signaling scaffold protein to mediate signal transduction. KAP1 is subjected to multiple post-translational modifications (PTMs), including serine/tyrosine phosphorylation, SUMOylation, and acetylation, which coordinately regulate KAP1 function and its protein abundance. KAP1 is involved in multiple aspects of cellular activities, including DNA damage response, virus replication, cytokine production and stem cell pluripotency. Moreover, knockout of KAP1 results in embryonic lethality, indicating that KAP1 is crucial for embryonic development and possibly impacts a wide-range of (patho)physiological manifestations. Indeed, studies World J Biol Chem 2014 August 26; 5(3): 308-320 ISSN 1949-8454 (online)

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“…TRIM26 is a member of the tripartite motif (TRIM) protein family composed of more than 70 members in human 29. In recent years, the TRIM protein family, such as TRIM3 , TRIM16 , TRIM28 , and TRIM40 , have been reported for their roles in cancers 30, 31, 32, 33. However, to date, its role in tumor remains unclear.…”

Section: Resultsmentioning

confidence: 99%

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response

et al. 2018

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The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two‐stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT‐PCR analysis (qRT‐PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10−19). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC.

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Tripartite Motif Containing 28 (Trim28) Can Regulate Cell Proliferation by Bridging HDAC1/E2F Interactions

Cited by 90 publications

References 48 publications

KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

KAP1 Is a Host Restriction Factor That Promotes Human Adenovirus E1B-55K SUMO Modification

KAPtain in charge of multiple missions: Emerging roles of KAP1

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response

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