Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis

Molinari, Marta; Mercurio, Ciro; Dominguez, Jorge; Goubin, F; Draetta, Giulio

doi:10.1093/embo-reports/kvd018

Cited by 190 publications

(192 citation statements)

References 34 publications

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“…It has been shown that the phosphorylation-dependent degradation of Cdc25A occurs in both normal interphase cells and S-phase cells subjected to different stress conditions. [33][34][35][36][37][38] Thus, a fixed threshold of Cdc25A activity is maintained in a normal cell cycle, and, in response to cell damage, the accelerated phosphorylation-dependent degradation of Cdc25A induces the inactivation of CDK complexes and the consequent arrest of cell division. Mitotic stabilization of Cdc25A also requires some phosphorylation events.…”

Section: Resultsmentioning

confidence: 99%

Human Cdc14A Reverses CDK1 Phosphorylation of Cdc25A on Serines 115 and 320

Esteban¹,

Vázquez-Novelle²,

Calvo³

et al. 2006

Cell Cycle

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Section: Resultsmentioning

confidence: 99%

Human Cdc14A Reverses CDK1 Phosphorylation of Cdc25A on Serines 115 and 320

Esteban¹,

Vázquez-Novelle²,

Calvo³

et al. 2006

Cell Cycle

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“…In addition, the destruction of Cyclin D inactivates Cdk4, which is then unable to phosphorylate pRb required to release the associated S phase Cyclin transcription factor E2F. Furthermore, active ATM-Chk2/ATR-Chk1 targeting of Cdc25A leads to the rapid destruction of phosphatase activity and consequently the levels of Cdk2 inhibitory phosphorylation increase (Molinari et al, 2000;Falck et al, 2001;Mailand et al, 2000). In combination, the negative regulation of Cdk2 contributes to G1 cell cycle arrest by preventing Cdk2 phosphorylation of Cdc45 and therefore, its loading onto orgins, which is required in the initiation of DNA replication (Costanzo et al, 2000;Broderick and Nasheuer, 2009).…”

Section: Dna Damage Checkpoint Responses Control Cell Cycle Progressimentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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“…1). Cdc25A is likely to be important for G1/S phase transition and in preserving genomic integrity (Jinno et al, 1994), although Cdc25A may also have some role in the initiation of mitosis (Molinari et al, 2000). Recent reports have shown that arylating K vitamin analogs, especially the prototype Cpd 5, can selectively inhibit Cdc25 activity in vitro and in cell cultures (Wu and Sun, 1999;Tamura et al, 2000;Wang et al, 2001).…”

Section: Mechanisms Of Cell Growth Inhibition By K Vitamin Analogs Prmentioning

confidence: 99%

“…Among them, Cdc25A dephosphorylates Cdk4/Cdk6 at their Thr-14 and Tyr-15 residues during the G1-S phase of the cell cycle and thus stimulate Cdk4/6 kinase activity (Jinno et al, 1994;Saha et al, 1997). Recent evidence also suggests that Cdc25A may have a role in the initiation of mitosis (Molinari et al, 2000).…”

Section: Cell Cycle Arrest By Thioalkyl K Vitamin Analogsmentioning

confidence: 99%

K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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The main function of K vitamins is to act as co-factors for g-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.

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Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis

Cited by 190 publications

References 34 publications

Human Cdc14A Reverses CDK1 Phosphorylation of Cdc25A on Serines 115 and 320

Human Cdc14A Reverses CDK1 Phosphorylation of Cdc25A on Serines 115 and 320

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

K vitamins, PTP antagonism, and cell growth arrest

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