Tip60 modulates PLAGL2‐mediated transactivation by acetylation

Ning, Jinying; Zheng, Gang; Yi, Yang

doi:10.1002/jcb.21444

Cited by 11 publications

(8 citation statements)

References 44 publications

(48 reference statements)

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“…The lack of NCF2 promoter-reporter activity by PLAGL2 alone, however, was not unprecedented, as similar results were reported for PLAGL2 transactivation of an IGF-II promoter-reporter (Ning et al, 2008). In those studies, overexpression of PLAGL2 had no significant effect on the activity of the IGF-II promoter-reporter, however, when PLAGL2 was overexpressed with Tip60, a PLAGL2-binding protein that modulates PLAGL2 transactivation through acetylation, the activity of the IGF-II promoter-reporter was stimulated approximately ~2 fold.…”

Section: Discussionsupporting

confidence: 81%

Modulation of PLAGL2 transactivation by positive cofactor 2 (PC2), a component of the ARC/Mediator complex

Wezensky

Hanks

Wilkison

et al. 2010

Gene

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The pleomorphic adenoma gene (PLAG) family of transcription factors regulate a wide-range of physiological processes, including cell proliferation, tissue-specific gene regulation, and embryonic development, although little is known regarding the mechanisms that regulate PLAG protein activity. In this study, a yeast two-hybrid screen identified PC2, a component of the Mediator complex, as a PLAGL2-binding protein. We show that PC2 cooperates with PLAGL2 and PU.1 to enhance the activity of a known PLAGL2 target promoter (NCF2). The PLAGL2 binding element in the NCF2 promoter consisted of the core sequence of the bipartite PLAG1 consensus site, but lacked the Gcluster motif, and was recognized by PLAGL2 zinc fingers 5 and 6. Promoter and PLAGL2 mutants showed that PLAGL2 and PU.1 were required to bind to their respective sites in the promoter, and PC2 knockdown demonstrated that PC2 was essential for enhanced promoter activity. Coimmunoprecipitation and promoter-reporter studies reveal that the effect of PC2 on PLAGL2 target promoter activity was conferred via the C-terminus of PLAGL2, the region that is required for PC2 binding and contains the PLAGL2 activation domain. Importantly, chromatin immunoprecipitation analysis and PC2 knockdown studies confirmed that endogenous PC2 protein associated with the NCF2 promoter in MM1 cells in the region occupied by PLAGL2, and was required for PLAGL2 target promoter activity in TNF-α-treated MM1 cells, respectively. Lastly, the expression of another known PLAGL2 target gene, insulin-like growth factor II (IGF-II), was greatly diminished in the presence of PC2 siRNA. Together, the data identify PC2 as a novel PLAGL2-binding protein and important mediator of PLAGL2 transactivation.

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Section: Discussionsupporting

confidence: 81%

Modulation of PLAGL2 transactivation by positive cofactor 2 (PC2), a component of the ARC/Mediator complex

Wezensky

Hanks

Wilkison

et al. 2010

Gene

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“…Forty-eight hours post transfection, the cells were processed as described in Figure 1 by that Tip60 can regulate posttranslational modifications of other proteins. 22 By mutational analysis, we separated the ability of Tip60 to bind Mdm2 from its ability to block neddylation. We therefore speculate that Tip60 does not simply act by binding Mdm2 but might in addition interact with a third partner to inhibit the ligation of Nedd8.…”

Section: Discussionmentioning

confidence: 99%

Specific inhibition of Mdm2-mediated neddylation by Tip60

Dohmesen

Koeppel²,

Dobbelstein³

2008

Cell Cycle

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Tip60 is a histone acetyl transferase (HAT) and a cofactor of transcription, but also an interaction partner of the Mdm2 oncoprotein. The functional consequences of this interaction are only partially understood and were further explored in this study. We found that Tip60 is capable of selectively inhibiting the Mdm2-mediated conjugation of Nedd8 to p53, whereas it did not affect p53 ubiquitination. In contrast, the known Mdm2 antagonist p14arf preferentially blocked Ubiquitin conjugation by Mdm2. To identify underlying mechanisms, we studied the intracellular localization of Tip60 and Mdm2. Both proteins relocalized each other to the PML nuclear bodies, but a similar localization pattern was observed even in the absence of PML. Analysis of Tip60 deletion mutants revealed that some mutants, while still interacting with Mdm2, failed to relocalize it and to inhibit Mdm2-mediated neddylation, suggesting that these two phenomena require biochemical activities in addition to the mere interaction between the two proteins. For both activities, the HAT domain of Tip60 was not required. We propose that Tip60 can act as a selective antagonist to Mdm2-mediated neddylation but not ubiquitination. Hence, the two different E3 ligase activities of Mdm2 can be regulated individually.

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“… 44 In fact, such cases have recently been reported for transcription factors ( e.g. , HIC1 and PLAGL2) 45,46 …”

Section: Age‐ and Calorie Restriction–related Changes In Protein Acetmentioning

confidence: 94%

“…44 In fact, such cases have recently been reported for transcription factors (e.g., HIC1 and PLAGL2). 45,46 Incidentally, we previously showed that CR suppresses the age-related increase in protein carbonylation in the mitochondria of rat liver. 47 As mentioned above, protein carbonyl groups are generated by oxidative modification of lysine, arginine, or proline.…”

Section: Age-and Calorie Restriction-related Changes In Protein Acetymentioning

confidence: 99%

Biological significance of protein modifications in aging and calorie restriction

Nakamura

Kawakami

Kametani

et al. 2010

Annals of the New York Academy of Sciences

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By virtue of the progress in proteomics, the involvement of posttranslational modifications in aging has been more clearly demonstrated in recent years. We describe here that (1) carbonylation, a hallmark of protein oxidation in general, is paradoxically decreased in histone with aging and increased by calorie restriction (CR), (2) acetylation of lysine 9 and phosphorylation of serine 10 in histone H3 are decreased and increased, respectively, with aging, and (3) the acetylation level of multiple extranuclear proteins decreases significantly with aging, and the change was not only retarded but increased remarkably by CR in rat liver. Based on these findings, we discuss possible implications of the posttranslational protein modifications in biochemical processes underlying aging and CR-induced extension of life span.

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Tip60 modulates PLAGL2‐mediated transactivation by acetylation

Cited by 11 publications

References 44 publications

Modulation of PLAGL2 transactivation by positive cofactor 2 (PC2), a component of the ARC/Mediator complex

Modulation of PLAGL2 transactivation by positive cofactor 2 (PC2), a component of the ARC/Mediator complex

Specific inhibition of Mdm2-mediated neddylation by Tip60

Biological significance of protein modifications in aging and calorie restriction

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