Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis

Busino, Luca; Chiesa, Massimo; Draetta, Giulio; Donzelli, Maddalena

doi:10.1038/sj.onc.1207394

Cited by 174 publications

(179 citation statements)

References 69 publications

(74 reference statements)

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“…35 In this study, we show that besides translation inhibition Roc-A induces a rapid degradation of Cdc25A via activation of ATM/ATR-Chk1/Chk2 kinases (Figs. 2c and 2d).…”

Section: Discussionmentioning

confidence: 52%

“…Protein synthesis was estimated by measuring the amount of incorporated 35 S-methionine. Briefly, cells (1 3 10 6 ) were incubated for 3 hr in methionine-free medium followed by adding 7 lCi per well of 35 S-methionine-labeling mix (PerkinElmer, Waltham, MA).…”

Section: Translation Assaymentioning

confidence: 99%

“…Briefly, cells (1 3 10 6 ) were incubated for 3 hr in methionine-free medium followed by adding 7 lCi per well of 35 S-methionine-labeling mix (PerkinElmer, Waltham, MA). After 2 to 6 hr incubation, cells were washed with PBS and lysed in ice-cold lysis buffer for 15 min on ice and the lysate was collected by centrifugation (10 min, 13,000 rpm).…”

Section: Translation Assaymentioning

confidence: 99%

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The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATRChk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

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“…35 In this study, we show that besides translation inhibition Roc-A induces a rapid degradation of Cdc25A via activation of ATM/ATR-Chk1/Chk2 kinases (Figs. 2c and 2d).…”

Section: Discussionmentioning

confidence: 52%

Section: Translation Assaymentioning

confidence: 99%

Section: Translation Assaymentioning

confidence: 99%

See 1 more Smart Citation

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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“…5 a and 5 b ). The stability of Cdc25A protein is largely regulated by the DNA damage response kinases ATM/ATR‐Chk1/Chk2 34. We show that TC induces a rapid activation of ATM/ATR‐Chk1/Chk2 kinases (Fig.…”

Section: Discussionmentioning

confidence: 62%

Mangrove dolabrane‐type of diterpenes tagalsins suppresses tumor growth viaROS‐mediated apoptosis and ATM/ATR–Chk1/Chk2‐regulated cell cycle arrest

Neumann

Yang

Köhler

et al. 2015

Intl Journal of Cancer

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Natural compounds are an important source for drug development. With an increasing cancer rate worldwide there is an urgent quest for new anti‐cancer drugs. In this study, we show that a group of dolabrane‐type of diterpenes, collectively named tagalsins, isolated from the Chinese mangrove genus Ceriops has potent cytotoxicity on a panel of hematologic cancer cells. Investigation of the molecular mechanisms by which tagalsins kill malignant cells revealed that it induces a ROS‐mediated damage of DNA. This event leads to apoptosis induction and blockage of cell cycle progression at S‐G2 phase via activation of the ATM/ATR—Chk1/Chk2 check point pathway. We further show that tagalsins suppress growth of human T‐cell leukemia xenografts in vivo. Tagalsins show only minor toxicity on healthy cells and are well tolerated by mice. Our study shows a therapeutic potential of tagalsins for the treatment of hematologic malignancies and a new source of anticancer drugs.

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“…The APC/C mediates degradation of Cdc25A starting at the end of mitosis throughout the G 1 phase, while the SCF complex plays a critical role in Cdc25A degradation in response to DNA damage. 10,44 Importantly, we found that loss of Importantly, we found that loss of we found that loss of loss of MIF uncouples Chk1/Chk2 checkpoints from proteasomal degradation of Cdc25A under conditions of DNA damage.…”

Section: Mif Is An Essential Component Of the G 2 M Dna Damage Checkpmentioning

confidence: 69%

Macrophage Migration Inhibitory Factor Coordinates DNA Damage Response with the Proteasomal Control of the Cell Cycle

Nemajerová¹,

Moll²,

Petrenko³

et al. 2007

Cell Cycle

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Proper repair of DNA damage is critical for protecting genomic stability, cellular viability and suppression of tumorigenesis. Both p53-dependent and p53-independent pathways have evolved to coordinate the cellular response following DNA damage. In this review, we highlight the importance of the ubiquitously expressed protein macrophage migration inhibitory factor (MIF) for an appropriate response to DNA damage. We discuss the mechanisms by which MIF affects the activity of the ubiquitin-proteasome system, and how this impacts on the integrity of the genome and on cancer.

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Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis

Cited by 174 publications

References 69 publications

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

Mangrove dolabrane‐type of diterpenes tagalsins suppresses tumor growth viaROS‐mediated apoptosis and ATM/ATR–Chk1/Chk2‐regulated cell cycle arrest

Macrophage Migration Inhibitory Factor Coordinates DNA Damage Response with the Proteasomal Control of the Cell Cycle

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