Repression of p53 activity by Smyd2-mediated methylation

Huang, Jing; Perez-Burgos, Laura; Placek, Brandon J.; Sengupta, Roopsha; Richter, Mario; Dorsey, Jean; Kubicek, Stefan; Opravil, Susanne; Jenuwein, Thomas; Berger, Shelley L.

doi:10.1038/nature05287

Cited by 568 publications

(638 citation statements)

References 14 publications

Supporting

Mentioning

608

Contrasting

Unclassified

Order By: Relevance

“…Table 1 lists proteins for which we have used strains of E. coli that over-express Hsp90 (Plus90α™; Plus90β™; Expression Technologies Inc., San Diego, CA) to prevent aggregation during expression [45][46][47][48][49][50][51][52]. This illustrates the structural and functional disparity among the in vitro clientele of Hsp90.…”

Section: Hsp90 Client Proteinsmentioning

confidence: 99%

Hsp90—From signal transduction to cell transformation

Brown

Zhu

Schmidt

et al. 2007

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

The molecular chaperone, Hsp90, facilitates the maturation and/or activation of over 100 'client proteins' involved in signal transduction and transcriptional regulation. Largely an enigma among the families of heat shock proteins, Hsp90 is central to processes broadly ranging from cell cycle regulation to cellular transformation. Here we review the contemporary body of knowledge regarding the biochemical mechanisms of Hsp90 and update the most current paradigms defining its involvement in both normal and pathological cell physiology. KeywordsHsp90; heat shock protein; molecular chaperone; ATPase; genetic capacitor Hsp90 defines a family of molecular chaperones that are highly conserved from prokaryotes to eukaryotes [1][2][3][4][5]. Nonessential for normal growth in most bacteria, Hsp90 is abundantly expressed in higher eukaryotes where it has been shown to be necessary for viability [6,7]. It functions as a homodimer that associates with co-chaperones to catalyze the maturation and/ or activation of over 100 substrate proteins that are known to be involved in cell regulatory pathways [5]. These 'client proteins' include protein kinases, nuclear hormone receptors, transcription factors, and an array of other essential proteins [8]. While much is known regarding the ATPase-driven conformational cycling of Hsp90, the precise physical effects imparted by this chaperone that serve to activate its substrates are still poorly understood [5]. Hsp90 architectureThree highly conserved domains comprise the structure of Hsp90. These include the N-terminal domain, responsible for ATP-binding, a proteolytically resistant core domain, and the Cterminal domain that facilitates homodimerization (Fig. 1a) [9]. In eukaryotes, a more variable charged region links the N-terminal domain to the core domain. The length and composition of this linker region is highly divergent among organisms [10]. As no atomic resolution structure for full-length Hsp90 is yet available, the most thorough structural analyses for Hsp90, to date, have been based on crystallographic studies of its individual domains.A mechanistic understanding of Hsp90 was nebulous until partial sequence homology was recognized between its N-terminal domain and two types of ATP-dependent proteins. These

show abstract

Section: Hsp90 Client Proteinsmentioning

confidence: 99%

Hsp90—From signal transduction to cell transformation

Brown

Zhu

Schmidt

et al. 2007

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…Multiple PTMs within one protein can coordinately determine a functional outcome, which is called PTM crosstalk (9). For example, the Set9-mediated methylation of Lys 372 on p53 inhibits the Smyd2-mediated methylation of Lys 370, and consequently represses the p53 activity (10). On histone H3, the methylation of Lys 4 by SET7 and Lys 9 by SUV39H1 was found to inhibit each other, which has differential effects on subsequent histone acetylation by p300 (11).…”

mentioning

confidence: 99%

Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

Huang

Xu²,

Zhou

et al. 2015

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Post-translational modification (PTM) 1 plays an important role in regulating the functions of proteins. PTMs of multiple residues on one protein may work together to determine a functional outcome, which is known as PTM crosstalk. Identification of PTM cross-talks is an emerging theme in proteomics and has elicited great interest, but their properties remain to be systematically characterized. To this end, we collected 193 PTM cross-talk pairs in 77 human proteins from the literature and then tested location preference and co-evolution at the residue and modification levels. We found that cross-talk events preferentially occurred among nearby PTM sites, especially in disordered protein regions, and cross-talk pairs tended to co-evolve. Given the properties of PTM cross-talk pairs, a naïve Bayes classifier integrating different features was built to predict cross-talks for pairwise combination of PTM sites. By using a 10-fold cross-validation, the integrated prediction model showed an area under the receiver operating characteristic (ROC) curve of 0.833, superior to using any individual feature alone. The prediction performance was also demonstrated to be robust to the biases in the collected PTM cross-talk pairs. The integrated approach has the potential for large-scale prioritization of PTM cross-talk candidates for functional validation and was implemented as a web server available at

show abstract

“…The retinoblastoma tumor suppressor protein (Rb) is monomethylated at K873 by SET7/9, which is required for Rb-dependent cell cycle arrest, transcriptional repression, and Rbdependent differentiation as well as interaction with the heterochromatin protein HP1 [10]. The Rb protein is also shown to be methylated at K860 by SMYD2, the same histone H3K4 methyltransferase that methylates p53 [19,34]. Methylation of K860 of Rb provides a direct bind- G9a, another histone-lysine methyltransferase, catalyzes mono-, di-, and tri-methylation of histone H3K9 [35,36].…”

Section: Lysine Methylation Of Nonhistone Proteinsmentioning

confidence: 99%

“…For p53, as summarized in a recent review [18], the reactions occur on K370, K372, and K382, with consequences for function that depend on the site and the degree of methylation. K370 is monomethylated by the H3K4 methylase SMYD2, leading to repression of transcription [19], and is dimethylated at this site by an unknown methylase. Dimethylation of K370 provides a binding site for the coactivator 53BP1 and thus is strongly activated.…”

Section: Lysine Methylation Of Nonhistone Proteinsmentioning

confidence: 99%

Lysine methylation of promoter-bound transcription factors and relevance to cancer

2010

View full text Add to dashboard Cite

p53, NFκB, STAT3, and several other transcription factors are reversibly methylated on lysine residues by enzymes that also modify histones. The methylations of NFκB and STAT3 take place when they are bound to promoters, suggesting a more general model in which the binding of inducible transcription factors to DNA helps to recruit chromatin-modification machinery, which then may modify not only histones but also the bound transcription factors. Mutations of some histone-lysine methyltransferases and demethylases are linked to cancer, and these mutations may alter the methylation not only of histones but also of transcription factors, and thus may be tumorigenic through more than one mechanism. In recent years, much attention has been focused on posttranslational modification of chromatin because of its critical role in regulating gene expression [1]. The N-terminal tails of histones, as well as positions in the globular domains, carry methylations, acetylations, phosphorylations, ADP ribosylations, ubiquitinations, sumoylations, and other modifications [2]. Many different amino acid residues of each of the four core histones have been identified as modification sites [3] and some lysine side chains can be methylated or acetylated alternatively. These modifications provide entry sites for accessory proteins that help to determine higher order chromatin organization, leading to the activation or inactivation of specific genes. The lysine ε-amino groups can receive one, two, or three methyl groups and the extent of lysine methylation at a single lysine residue can be read differently by different effector proteins [4]. H3K4 methylation is associated with an early-elongating form of RNA polymerase II at actively transcribed genes, H3K9 and H3K27 methylation are linked to heterochromatin formation, while H3K36 methylation provides a stable molecular mechanism for establishing chromatin context throughout the genome by distinguishing potential regulatory regions from transcribed chromatin [5]. Moreover, increasing evidence indicates that nonhistone proteins are subject to reversible acetylation or methylation by histone-modifying enzymes. Among these nonhistone targets are transcription factors, hormone receptors, signal transducers, chaperones, and proteins of the cytoskeleton [6][7][8][9][10][11][12]. Although the acetylation of nonhistone proteins has been appreciated for some time [9,13,14], their methylation has been recognized only more recently. Here, we provide a summary of recent work showing lysine methylation of transcription factors that have well-recognized roles in tumorigenesis and of the effects of mutations of lysine methyltransferases and demethylases in cancer, and we cite evidence that at least some modifications take place only on promoter-bound transcription factors. Lysine methylation of nonhistone proteinsReversible modification of histones by methylation and demethylation, which occur at both lysine and arginine residues, plays an important role in many biological processes, including transcri...

show abstract

Repression of p53 activity by Smyd2-mediated methylation

Cited by 568 publications

References 14 publications

Hsp90—From signal transduction to cell transformation

Hsp90—From signal transduction to cell transformation

Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

Lysine methylation of promoter-bound transcription factors and relevance to cancer

Contact Info

Product

Resources

About