Timing of Events in Mitosis

Georgi, Ann; Stukenberg, P. Todd; Kirschner, Marc W.

doi:10.1016/s0960-9822(01)00662-5

Cited by 56 publications

(42 citation statements)

References 54 publications

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“…As demonstrated by Sampath et al (54), autocatalytic methylation of H3K9 G9a methylase is necessary to mediate in vivo interaction with heterochromatin protein 1 (HP1), and this methyl-dependent interaction can be reversed by adjacent G9a phosphorylation. Similar phosphorylation at G 2 /M phase has been reported for PR-Set7 H4K20 methylase, and its catalytic function is known to play a critical role in mitosis and S phase progression (55)(56)(57).…”

Section: Discussionsupporting

confidence: 69%

Phosphorylation of Mixed Lineage Leukemia 5 by Cdc2 Affects Its Cellular Distribution and Is Required for Mitotic Entry

Liu

Wang

Cheng

et al. 2010

Journal of Biological Chemistry

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The human mixed lineage leukemia-5 (MLL5) gene is frequently deleted in myeloid malignancies. Emerging evidence suggests that MLL5 has important functions in adult hematopoiesis and the chromatin regulatory network, and it participates in regulating the cell cycle machinery. Here, we demonstrate that MLL5 is tightly regulated through phosphorylation on its central domain at the G 2 /M phase of the cell cycle. Upon entry into mitosis, the phosphorylated MLL5 delocalizes from condensed chromosomes, whereas after mitotic exit, MLL5 becomes dephosphorylated and re-associates with the relaxed chromatin. We further identify that the mitotic phosphorylation and subcellular localization of MLL5 are dependent on Cdc2 kinase activity, and Thr-912 is the Cdc2-targeting site. Overexpression of the Cdc2-targeting MLL5 fragment obstructs mitotic entry by competitive inhibition of the phosphorylation of endogenous MLL5. In addition, G 2 phase arrest caused by depletion of endogenous MLL5 can be compensated by exogenously overexpressed full-length MLL5 but not the phosphodomain deletion or MLL5-T912A mutant. Our data provide evidence that MLL5 is a novel cellular target of Cdc2, and the phosphorylation of MLL5 may have an indispensable role in the mitotic progression.Aberrations in chromosome 7, either due to monosomy or partial deletion of 7q, are commonly associated with myeloid malignancies, including myelodyplastic syndrome, acute myeloid leukemia, and therapy-induced myeloid neoplasms (1, 2). Cytogenetic studies have delineated 7q22 as a critical region in myeloid malignancies (3-5). A search for a candidate tumor suppressor gene within this region led to the identification of a novel gene, which was later categorized as the fifth MLL/trithorax member and designated MLL5 (6). MLL1 (also known as ALL-1, HRX, and Htrx), a frequent target of chromosomal translocation in myeloid and lymphoid leukemia, is the best characterized member of the MLL protein family (7-9). Mll1 and Mll2 knock-out mice are embryonic lethal (10, 11). Mice carrying mutant Mll3 genes are partially embryonic lethal, and surviving mice are stunted in overall growth (12). Recent studies on Mll5 knock-out mice have revealed that MLL5 plays a critical role in adult hematopoiesis and appears to be dispensable for embryonic development (13-16). Although Mll5 knockout mice do not have an increased incidence of tumors, they suffer from mild growth retardation, male infertility, and compromised immunity. Nonetheless, the physiological function of MLL5 and its cellular targets remain elusive.A common feature of the MLL protein family is the concomitant presence of a variable number of PHD 3 (plant homeodomain) zinc fingers and a single SET (Su (var) 3-9, enhancer-ofzeste and trithorax) domain. Reports have shown that PHD fingers are binding or recognition modules for histone modification (17), whereas the SET domain possesses methyltransferase activity (18,19). MLL1 and MLL2 form a protein complex containing menin, WDR5, and chromatin-remodeling components and are ...

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Section: Discussionsupporting

confidence: 69%

Phosphorylation of Mixed Lineage Leukemia 5 by Cdc2 Affects Its Cellular Distribution and Is Required for Mitotic Entry

Liu

Wang

Cheng

et al. 2010

Journal of Biological Chemistry

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“…Thus, different numbers of available phosphosites combined with varying localization may provide temporal control in ultrasensitive activation of different Cdc25 isoforms. Beside multisite phosphorylation, other mechanisms also may contribute to the ultrasensitive responses of Cdc25 to Cdk1, such as competition among Cdk1 substrates and protein phosphoisoforms for enzyme binding (6,30) and regulation of opposing enzymes like Clp1 (31).…”

Section: Discussionmentioning

confidence: 99%

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Lu¹,

Domingo-Sananes

Huzarska³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cyclin-dependent kinase 1 (Cdk1) kinase dephosphorylation and activation by Cdc25 phosphatase are essential for mitotic entry. Activated Cdk1 phosphorylates Cdc25 and other substrates, further activating Cdc25 to form a positive feedback loop that drives the abrupt G2/mitosis switch. Conversely, mitotic exit requires Cdk1 inactivation and reversal of Cdk1 substrate phosphorylation. This dephosphorylation is mediated, in part, by Clp1/Cdc14, a Cdk1-antagonizing phosphatase, which reverses Cdk1 phosphorylation of itself, Cdc25, and other Cdk1 substrates. Thus, Cdc25 phosphoregulation is essential for proper G2-M transition, and its contributions to cell cycle control have been modeled based on studies using Xenopus and human cell extracts. Because cell extract systems only approximate in vivo conditions where proteins interact within dynamic cellular environments, here, we use Schizosaccharomyces pombe to characterize, both experimentally and mathematically, the in vivo contributions of Cdk1-mediated phosphorylation of Cdc25 to the mitotic transition. Through comprehensive mapping of Cdk1 phosphosites on Cdc25 and characterization of phosphomutants, we show that Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation, the precision of mitotic entry, and unvarying cell length but not Cdc25 localization or abundance. We propose a mathematical model that explains Cdc25 regulation by Cdk1 through a distributive and disordered phosphorylation mechanism that ultrasensitively activates Cdc25. We also show that Clp1/Cdc14 dephosphorylation of Cdk1 sites on Cdc25 controls the proper timing of cell division, a mechanism that is likely due to the double negative feedback loop between Clp1/Cdc14 and Cdc25 that controls the abruptness of the mitotic exit switch. mitotic bistability | multisite phosphorylation

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“…Irrespective of whether it is the Ca 2+ -releasing activity, co-factors or substrates that are sequestered and released from nuclei, this nuclear compartmentalization-mediated regulation of Ca 2+ release represents a new mechanism for regulating Ca 2+ oscillations in cells. In particular, it may prove important in stimulating mitotic Ca 2+ transients in other systems that could play a role in the coordination of the complex series of events that take place during mitosis (Groigno and Whitaker, 1998;Georgi et al, 2002).…”

Section: A Nuclear Compartmentalization Model For the Regulation Of Cmentioning

confidence: 99%

Ca2+ oscillations at fertilization in mammals are regulated by the formation of pronuclei

2003

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In mammals, the sperm triggers a series of cytosolic Ca2+oscillations that continue for ∼4 hours, stopping close to the time of pronucleus formation. Ca2+ transients are also seen in fertilized embryos during the first mitotic division. The mechanism that controls this pattern of sperm-induced Ca2+ signalling is not known. Previous studies suggest two possible mechanisms: first, regulation of Ca2+oscillations by M-phase kinases; and second, regulation by the presence or absence of an intact nucleus. We describe experiments in mouse oocytes that differentiate between these mechanisms. We find that Ca2+oscillations continue after Cdk1-cyclin B1 activity falls at the time of polar body extrusion and after MAP kinase has been inhibited with UO126. This suggests that M-phase kinases are not necessary for continued Ca2+oscillations. A role for pronucleus formation in regulating Ca2+signalling is demonstrated in experiments where pronucleus formation is inhibited by microinjection of a lectin, WGA, without affecting the normal inactivation of the M-phase kinases. In oocytes with no pronuclei but with low M-phase kinase activity, sperm-induced Ca2+ oscillations persist for nearly 10 hours. Furthermore, a dominant negative importin β that inhibits nuclear transport, also prevents pronucleus formation and causes Ca2+ oscillations that continue for nearly 12 hours. During mitosis, fluorescent tracers that mark nuclear envelope breakdown and the subsequent reformation of nuclei in the newly formed two-cell embryo establish that Ca2+ oscillations are generated only in the absence of a patent nuclear membrane. We conclude by suggesting a model where nuclear sequestration and release of a Ca2+-releasing activity contributes to the temporal organization of Ca2+ transients in meiosis and mitosis in mice.

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Timing of Events in Mitosis

Cited by 56 publications

References 54 publications

Phosphorylation of Mixed Lineage Leukemia 5 by Cdc2 Affects Its Cellular Distribution and Is Required for Mitotic Entry

Phosphorylation of Mixed Lineage Leukemia 5 by Cdc2 Affects Its Cellular Distribution and Is Required for Mitotic Entry

Multisite phosphoregulation of Cdc25 activity refines the mitotic entrance and exit switches

Ca2+ oscillations at fertilization in mammals are regulated by the formation of pronuclei

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