Lysine methylation regulates the pRb tumour suppressor protein

Munro, Shonagh; Khaire, Nandkumar; Inche, A; Carr, Simon M.; Thangué, Nicholas B. La

doi:10.1038/onc.2009.511

Cited by 97 publications

(110 citation statements)

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“…Likewise, when pRb is targeted by methylation and acetylation, phosphorylation is reduced. Further, methylated lysine residues can serve as docking sites for 'reader' effector proteins such as HP1 and L3MBTL1, which have both been shown to bind to methylated pRb and augment repression activity (Munro et al, 2010;Saddic et al, 2010) (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…A large number of methyltransferases have been identified, which can loosely be divided into two subgroups; lysine methyltransferases, mostly belonging to the SET domain family (Martin and Zhang, 2005), and arginine methyltransferase, referred to as protein arginine dimethyltransferases (Bedford and Clarke, 2009). Very interestingly, pRb is methylated by the mono-methyltransferase Set7/9 at two distinct lysine residues within the C-terminal domain of pRb, K873 and K810 (Munro et al, 2010;Carr et al, 2011) (Figure 1). Methylation of pRb at K873 creates a binding site for the heterochromatin protein, HP1.…”

Section: Prb Methylationmentioning

confidence: 99%

“…Methylation of pRb at K873 creates a binding site for the heterochromatin protein, HP1. HP1 is involved with gene silencing and transcriptional inactivity (Fischle et al, 2003;Hediger and Gasser, 2006), and indeed when methylation of pRb is prevented an increase in the expression of E2F target genes such as DHFR, Cdc6 and E2F-1 occurs (Munro et al, 2010). In addition, methylation at K873 can influence cell cycle progression; a mutant-derivative pRb lacking methylation at K873 displayed reduced ability to cause cell cycle arrest when compared with the wild-type counterpart.…”

Section: Prb Methylationmentioning

confidence: 99%

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Diversity within the pRb pathway: is there a code of conduct?

2012

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The failure of cell proliferation to be properly regulated is a hallmark of tumourigenesis. The retinoblastoma protein (pRb) pathway represents a key component in the regulation of the cell cycle and tumour suppression. Recent findings have revealed new levels of complexity reflecting a repertoire of post-translational modifications that occur on pRb together with its key effector E2F-1. Here we provide an overview of the modifications and consider the possibility of a 'code' that endows pRb with the ability to function in diverse physiological settings.

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Section: Discussionmentioning

confidence: 99%

Section: Prb Methylationmentioning

confidence: 99%

Section: Prb Methylationmentioning

confidence: 99%

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Diversity within the pRb pathway: is there a code of conduct?

2012

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“…25 Apart from the phosphorylation, methylation of RB has emerged as an important modification in recent years; for example, three lysine residues (K810, K873 and K860) within the C-terminal domain of RB have been reported to be methylated. [25][26][27] Particularly, the methylation of K810 residue has been found to bring about variable effects on the function of RB. For instance, methylation of K810 by SET domain containing protein 7 (Set7/9) retains the hypophosphorylated status of RB and suppresses the cellular growth in U2OS cells.…”

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confidence: 99%

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

et al. 2015

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Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which can stabilize the state of senescence. The retinoblastoma (RB) protein has an important role in SAHF; cells that lack active RB pathway fail to form SAHF. It has been known that the posttranslational modifications of RB, for example, phosphorylation, regulate its function. To date, whether methylation of RB impacts on the SAHF formation is unknown. Here we report that JMJD3, a histone demethylase catalyzing the tri-methylation of H3K27 (H3K27me3), can demethylate the nonhistone protein RB at the lysine810 residue (K810), which is a target of the methyltransferase Set7/9. We detected a significant upregulation of JMJD3 during cellular senescence and SAHF formation in WI38 cells induced by H-RasV 12 , and we found that ectopic expression of JMJD3 promoted cellular senescence and SAHF formation in WI38 cells. Furthermore, during the process of SAHF assembly, JMJD3 was transported to the cytoplasm and interacted with RB through its demethylase domain JmjC. Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly. This study highlights the role of JMJD3 as a novel inducer of SAHF formation through demethylating RB and provides new insights into the mechanisms of cellular senescence and SAHF assembly. Cellular senescence is an irreversible process of cell cycle arrest. The senescent cells remain metabolically active but are unable to express genes required for cell proliferation. 1,2 The known causes of cellular senescence include telomere shortening, oxidative stress, DNA damage and hyperoncogenic signaling. 3 H-RasV 12 has been used as a model to induce senescence in normal cells. [4][5][6] Senescent cells are typically characterized by a large flat morphology and the expression of a senescence-associated β-galactosidase activity (SA-β-gal), and nuclei of senescence cells may remodel to form the heterochromatin structures termed the senescenceassociated heterochromatin foci (SAHF). 7 SAHF are condensed regions of DNA that correlate with transcriptionally inactive sites. 8 These heterochromatin foci are hallmarked by H3K9me3 and the incorporation of heterochromatin protein HP1, macroH2A, PML (promyelocy leukemia protein) and HMGA1 (high mobility group AT-hook 1). 7,9-11 Recently, it has been shown that repressive markers, such as H3K9me3, H3K9me2 and H3K27me3, are rearranged into the nonoverlapping structural layers in SAHF. 12-14 Changes of heterochromatin organization generate a repressive chromatin environment that prevents transcription of genes that promote growth, thereby stabilize the state of senescence. 7,15 The retinoblastoma (RB) tumor suppressor is an important senesc...

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“…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.…”

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confidence: 99%

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

2010

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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...

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Lysine methylation regulates the pRb tumour suppressor protein

Cited by 97 publications

References 44 publications

Diversity within the pRb pathway: is there a code of conduct?

Diversity within the pRb pathway: is there a code of conduct?

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

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

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