Phosphorylation at Serine 75 Is Required for UV-mediated Degradation of Human Cdc25A Phosphatase at the S-phase Checkpoint

Hassepass, Ingo; Voit, Renate; Hoffmann, Ingrid

doi:10.1074/jbc.m302704200

Cited by 74 publications

(78 citation statements)

References 21 publications

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“…This phosphorylation is required for Chk1-induced degradation of Cdc25A and primes Cdc25A for degradation both in a normal cell cycle and in response to DNA damage. Indeed, the homologous serine in human Cdc25A (Ser 76) was found by Hassepass et al (2003) to be a Chk1 phosphorylation site in vitro. The same group demonstrated that Ser 76 mediates Cdc25A stabilization in response to UV-induced DNA damage.…”

Section: Cdc25a and Checkpointsmentioning

confidence: 99%

Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis

et al. 2004

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In eukaryotic cells, control mechanisms of cell-cycle progression have evolved to accurately monitor the integrity of genetic information to be transferred to the progeny. Cdc25A phosphatase is an essential activator of cell-cycle progression and is targeted by checkpoint signals. Ubiquitylation regulates Cdc25A activity through fine tuning of its protein levels. Two different ubiquitin ligases (APC/C and SCF complex) are involved in Cdc25A turnover. While APC/C is involved in regulating Cdc25A at the exit of mitosis, SCF regulates the abundance of Cdc25A in S phase and G2. In response to DNA damage or to stalled replication, the activation of the ATM and ATR protein kinases leads to Chk1 and Chk2 activation and to Cdc25A hyperphosphorylation. These events stimulate SCF-mediated ubiquitylation of Cdc25A and its proteolysis. This contributes to delaying cell-cycle progression, thereby preventing genomic instability. Based on recent findings, we discuss the role of Cdc25A ubiquitylation and degradation in cell-cycle progression and in response to DNA damage. Moreover, we discuss the role of phosphorylation at multiple sites in triggering ubiquitylation signals.

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Section: Cdc25a and Checkpointsmentioning

confidence: 99%

Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis

et al. 2004

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“…Loss-Chk1-mediated Cdc25A phosphorylation leads to Cdc25A proteolytic destruction, thereby blocking cell cycle progression (24,27,(65)(66)(67). To explore whether 17-AAG-induced Chk1 loss affects Cdc25A destruction, we treated HeLa cells with 17-AAG for 1 h and then with gemcitabine for an additional 4 h and examined Cdc25A levels (Fig.…”

Section: -Aag-mediated Chk1 Loss Blocks Cdc25amentioning

confidence: 99%

Hsp90 Inhibition Depletes Chk1 and Sensitizes Tumor Cells to Replication Stress

Arlander¹,

Eapen²,

Vroman³

et al. 2003

Journal of Biological Chemistry

163

148

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DNA damage and replication stress activate the Chk1 signaling pathway, which blocks S phase progression, stabilizes stalled replication forks, and participates in G 2 arrest. In this study, we show that Chk1 interacts with Hsp90, a molecular chaperone that participates in the folding, assembly, maturation, and stabilization of specific proteins known as clients. Consistent with Chk1 being an Hsp90 client, we also found that Chk1 but not Chk2 is destabilized in cells treated with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). 17-AAG-mediated Chk1 loss blocked the ability of Chk1 to target Cdc25A for proteolytic destruction, demonstrating that the Chk1 signaling pathway was disrupted in the 17-AAG-treated cells. Finally, 17-AAG-mediated disruption of Chk1 activation dramatically sensitized various tumor cells to gemcitabine, an S phase-active chemotherapeutic agent. Collectively, our studies identify Chk1 as a novel Hsp90 client and suggest that pharmacologic inhibition of Hsp90 may sensitize tumor cells to chemotherapeutic agents by disrupting Chk1 function during replication stress.

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“…During the S phase, SCF ␤-TRCP regulates Cdc25A degradation in an unperturbed cell division cycle and in response to DNA damage, requiring phosphorylation of serines 76, 79, 82, and 85 (13)(14)(15). The Cdc25A destruction induced by ionizing and UV irradiation requires the phosphorylation of Ser-123 mediated by the ATM/Chk2 or ATR/Chk1 pathway (7,16,17) and the phosphorylation of Ser-76, respectively (18,19). Rapid Cdc25A degradation in response to DNA damage is a part of the DNA damage checkpoint mechanism that protects genomic integrity by arresting the cell cycle progression and allowing cells to repair damaged DNA.…”

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confidence: 99%

Pro-apoptotic Role of Cdc25A

Chou

Yen

Lee³

et al. 2010

Journal of Biological Chemistry

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Cdc25A is a dual specificity protein phosphatase that activates cyclin/cyclin-dependent protein kinase (Cdk) complexes by removing inhibitory phosphates from conserved threonine and tyrosine in Cdks. To address how Cdc25A promotes apoptosis, Jurkat cells were treated with staurosporine, an apoptosis inducer. Upon staurosporine treatment, a Cdc25A C-terminal 37-kDa fragment, designated C37, was generated by caspase cleavage at Asp-223. Thr-507 in C37 became dephosphorylated, which prevented 14-3-3 binding, as shown previously. C37 exhibited higher phosphatase activity than full-length Cdc25A. C37 with alanine substitution for Thr-507 (C37/T507A) that imitated the cleavage product during staurosporine treatment interacted with Cdc2, Cdk2, cyclin A, and cyclin B1 and markedly activated cyclin B1/Cdc2. The dephosphorylation of Thr-507 might expose the Cdc2/Cdk2-docking site in C37. C37/ T507A also induced apoptosis in Jurkat and K562 cells, resulting from activating cyclin B1/Cdc2 but not Cdk2. Thus, this study reveals that Cdc25A is a pro-apoptotic protein that amplifies staurosporine-induced apoptosis through the activation of cyclin B1/Cdc2 by its C-terminal domain.

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Phosphorylation at Serine 75 Is Required for UV-mediated Degradation of Human Cdc25A Phosphatase at the S-phase Checkpoint

Cited by 74 publications

References 21 publications

Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis

Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis

Hsp90 Inhibition Depletes Chk1 and Sensitizes Tumor Cells to Replication Stress

Pro-apoptotic Role of Cdc25A

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