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EDITORIAL FOCUS
University of Nice-Sophia Antipolis, Institute of Developmental Biology and Cancer Research, UMR Centre National de la Recherche Scientifique (CNRS) 6543, Nice, France
THE DNA OF EUKARYOTIC CELLS is highly folded and compacted into chromatin that can be propagated during mitosis. Chromatin contains the entire genome and histones that are subjected to different posttranslational modifications, generally in the amino-terminal domain. Distinct modifications including acetylation, methylation, ubiquitination, ADP-ribosylation, glycosylation, and phosphorylation dictate dynamic transitions between transcriptionally active or silent chromatin states. The combinatorial nature of histone modifications defines the "histone code" proposed by Jenuwein and Allis (7), which considerably increases the information potential of the genetic code. Particular attention has been focused on histone H3 (H3) phosphorylation on serine 10 (Ser 10) since it is associated with chromosome condensation and segregation during mitosis (6). The development of specific antibodies for Ser 10 has allowed detailed analysis of H3 phosphorylation during the cell cycle. It begins during prophase with peak levels detected during metaphase, followed by a general decrease in the amount of phosphorylation during the progression through the cell cycle to telophase. This simple observation suggests the existence of a tightly controlled balance of kinase(s) and phosphatase(s), which governs the ratio of "opened or closed" chromatin. Members of the aurora AIR-2-Ipl1 kinase family have been found to control H3 phosphorylation during mitosis in different organisms (2, 4, 5). However, Ser 10 phosphorylation could take place upon different physiological stimuli, to induce chromatin decondensation for rapid induction of transcription. This rapid change in the transcription status was called the nucleosomal response by Mahadevan et al. (12), who described an increase in H3 phosphorylation with a concomitant induction of c-fos and c-jun genes upon stimulation of fibroblasts by growth factors, phorbol esters, inhibitors of protein synthesis, and inhibitors of protein phosphatases. This stimulation-dependent phosphorylation of H3 is rapid and transient and affects a population of H3 that differs from that detected in dividing cells. These results imply that Ser 10 could be phosphorylated by kinases other than the aurora kinases, depending on the stimulus and the targeted cells. Ser 10 lies within a consensus phosphorylation site by PKA (RXS), which is compatible with increased phosphorylation of Ser 10 following treatment of ovarian granulosa cells with follicle-stimulating-hormone (FSH) in a PKA-dependent manner (3). Ribosomal S6 serine-threonine kinase 2 and mitogen and stress response kinases (MSK1 and MSK2) have also been suggested to phosphorylate Ser 10 in patients with Coffin-Lowry syndrome or in Ras-transformed cells or in mice lacking MSK1 and MSK2 (16, 18, 19). Rapid induction of Ser 10 phosphorylation in response to the inflammatory agent TNF-
has also been described but involves the I
B kinase- (IKK-). Thus, IKK- represents another putative H3 kinase.
Whereas H3 phosphorylation has been studied in depth, the phosphatases responsible for its dephosphorylation have not been fully identified, although Murnion et al. (13) and Nowak et al. (14) reported that protein phosphatase 1 and protein phosphatase 2A (13, 14) are potential candidates for such a role. Kinney and coworkers have previously shown that VEGF and thrombin transiently induce MAP kinase phosphatase-1 (MKP-1) in endothelial cells (10) and that MKP-1 plays an important role in ex vivo angiogenesis and endothelial cell migration. This is not surprising since MKP-1 is a nuclear protein that is encoded by an immediate early gene (20). Interestingly, the same authors now provide strong arguments suggesting that MKP-1 but not MKP-2 transiently dephosphorylates H3 on Ser 10 after stimulation of endothelial cells by VEGF or thrombin (11). Ser 10 dephosphorylation is specific since threonine 3 (Thr 3), another H3 residue that is phosphorylated during mitosis (15), is not affected by MKP-1 in vivo nor in in vitro assays. These results represent a breakthrough in the field of cell signaling since the only known substrates for MKP-1 and the others members of this family of phosphatases are MAP kinase (MAPK) family members ERK, p38 or JNK. The MKP family members are dual specific phosphatases or DUSP that dephosphorylate threonine and tyrosine residues on MAPK, rendering the enzymes inactive. Hence, the capacity to dephosphorylate a serine residue is particularly intriguing even though MKP-1 has a shallow active site cleft that can dephosphorylate threonine tyrosine and serine residues (1). MKP-1 is considered by the authors as "a temporal repressor or modulator, to control access of the transcriptional machinery to the promoters of inflammatory genes." This is really a new concept in cell signaling since MKP/DUSP were considered as regulators of gene expression by modulating ERK, p38, or JNK pathways (9) even though the JNK signaling pathway is implicated in histone H3 phosphorylation on Ser 10 after stimulation by nickel (8). Activation of these different sets of kinases regulates the phosphorylation of numerous transcription factors, hence modulating their DNA binding or transactivation activity. By targeting an essential regulator of gene expression through modulation of chromatin condensation, MKP-1 and potentially others members of the DUSP family modulate the accessibility of the transcription machinery on a specific subset of genes essential for physiological purposes. The substrate-trapping technique initially described by Slack and coworkers (17) and used by Kinney et al. (11) could be used to determine whether other histones of the nucleosome (histones H2A, H2B, H3, and H4) could be DUSP targets, depending on the cell type or the pathophysiological situation, although some DUSP such as MKP-3/DUSP-6 have been described as nucleo cytoplasmic shuttling proteins. It would also be interesting to determine whether MKP-1 modulates chromatin condensation on its own promoter in a time- and stimulus-dependent manner.
The results of Kinney et al. (11) have to be confirmed by other studies but represent a very interesting finding that highlights a new way to explain the temporal regulation of gene expression in normal and pathological situations. This study addresses an interesting link between cell signaling and epigenetic phenomena, a domain that is poorly investigated. Figure 1 summarizes this new finding.
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2. De la Barre AE, Gerson V, Gout S, Creaven M, Allis CD, Dimitrov S. Core histone N-termini play an essential role in mitotic chromosome condensation. EMBO J 19: 379–391, 2000.[CrossRef][Web of Science][Medline]
3. DeManno DA, Cottom JE, Kline MP, Peters CA, Maizels ET, Hunzicker-Dunn M. Follicle-stimulating hormone promotes histone H3 phosphorylation on serine-10. Mol Endocrinol 13: 91–105, 1999.
4. De Souza CP, Osmani AH, Wu LP, Spotts JL, Osmani SA. Mitotic histone H3 phosphorylation by the NIMA kinase in Aspergillus nidulans. Cell 102: 293–302, 2000.[CrossRef][Web of Science][Medline]
5. Giet R, Glover DM. Drosophila aurora B kinase is required for histone H3 phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J Cell Biol 152: 669–682, 2001.
6. Gurley LR, D'Anna JA, Barham SS, Deaven LL, Tobey RA. Histone phosphorylation and chromatin structure during mitosis in Chinese hamster cells. Eur J Biochem 84: 1–15, 1978.[Web of Science][Medline]
7. Jenuwein T, Allis CD. Translating the histone code. Science 293: 1074–1080, 2001.
8. Ke Q, Li Q, Ellen TP, Sun H, Costa M. Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating JNK-MAPK pathway. Carcinogenesis 29: 1276–1281, 2008.
9. Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev 27: 253–261, 2008.[CrossRef][Web of Science][Medline]
10. Kinney CM, Chandrasekharan UM, Mavrakis L, DiCorleto PE. VEGF and thrombin induce MKP-1 through distinct signaling pathways: role for MKP-1 in endothelial cell migration. Am J Physiol Cell Physiol 294: C241–C250, 2008.
11. Kinney CM, Chandrasekharan UM, Yang L, Shen J, Kinter M, McDermott MS, DiCorleto PE. Histone H3 as a novel substrate for MAP kinase phosphatase-1. Am J Physiol Cell Physiol (November 19, 2008). doi:10.1152/ajpcell.00492.2008.
12. Mahadevan LC, Willis AC, Barratt MJ. Rapid histone H3 phosphorylation in response to growth factors, phorbol esters, okadaic acid, and protein synthesis inhibitors. Cell 65: 775–783, 1991.[CrossRef][Web of Science][Medline]
13. Murnion ME, Adams RR, Callister DM, Allis CD, Earnshaw WC, Swedlow JR. Chromatin-associated protein phosphatase 1 regulates aurora-B and histone H3 phosphorylation. J Biol Chem 276: 26656–26665, 2001.
14. Nowak SJ, Pai CY, Corces VG. Protein phosphatase 2A activity affects histone H3 phosphorylation and transcription in Drosophila melanogaster. Mol Cell Biol 23: 6129–6138, 2003.
15. Polioudaki H, Markaki Y, Kourmouli N, Dialynas G, Theodoropoulos PA, Singh PB, Georgatos SD. Mitotic phosphorylation of histone H3 at threonine 3. FEBS Lett 560: 39–44, 2004.[CrossRef][Web of Science][Medline]
16. Sassone-Corsi P, Mizzen CA, Cheung P, Crosio C, Monaco L, Jacquot S, Hanauer A, Allis CD. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science 285: 886–891, 1999.
17. Slack DN, Seternes OM, Gabrielsen M, Keyse SM. Distinct binding determinants for ERK2/p38alpha and JNK MAP kinases mediate catalytic activation and substrate selectivity of MAP kinase phosphatase-1. J Biol Chem 276: 16491–16500, 2001.
18. Soloaga A, Thomson S, Wiggin GR, Rampersaud N, Dyson MH, Hazzalin CA, Mahadevan LC, Arthur JS. MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J 22: 2788–2797, 2003.[CrossRef][Web of Science][Medline]
19. Strelkov IS, Davie JR. Ser-10 phosphorylation of histone H3 and immediate early gene expression in oncogene-transformed mouse fibroblasts. Cancer Res 62: 75–78, 2002.
20. Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 75: 487–493, 1993.[CrossRef][Web of Science][Medline]
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