Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation

Bernardi, Rosa; Liebermann, Dan A.; Hoffman, Barbara

doi:10.1038/sj.onc.1203564

Cited by 66 publications

(52 citation statements)

References 41 publications

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“…The S-phase progression is regulated by the activation of Cdk2/cyclin E by the Cdc25A phosphatase (Donzelli and Draetta, 2003). When the S-phase checkpoint is triggered, Cdc25A itself becomes phosphorylated and is thereby targeted for proteosome-dependent degradation (Bernardi et al, 2000;Mailand et al, 2000). Cdc25A is phosphorylated by Chk1 (Sanchez et al, 1997) and this highly conserved signaling event has been shown to affect Cdc25A protein turnover after IR as well as during unperturbed S phase (Sorensen et al, 2003).…”

Section: Ir-dependent S-phase Checkpoint Is Intact In Atr-deficient Cmentioning

confidence: 99%

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation

2006

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The vast majority of cancer cells have defective checkpoints that permit the cell cycle to progress in the presence of double-strand DNA breaks (DSBs) caused by ionizing radiation (IR) and radiomimetic drugs. ATR (ataxia telangiectasia-mutated and Rad3-related) has recently been shown to be activated by DSBs, although the consequences of this activity are largely unknown. In this report, we use advanced gene targeting methods to generate biallelic hypomorphic ATR mutations in human colorectal cancer cells and demonstrate that progression of the cancer cell cycle after IR treatment requires ATR. Cells with mutant ATR accumulated at a defined point at the beginning of the S phase after IR treatment and were unable to progress beyond that point, whereas cells at later stages of the S phase during the time of irradiation progressed and completed DNA replication. The prolonged arrest of ATR mutant cancer cells did not involve the ataxia telangiectasia mutated-dependent S-phase checkpoint, but rather closely resembled a previously characterized form of cell cycle arrest termed S-phase stasis. As ATR strongly contributed to clonogenic survival after IR treatment, these data suggest that blocking ATR activity might be a useful strategy for inducing S-phase stasis and promoting the radiosensitization of checkpointdeficient cancer cells.

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Section: Ir-dependent S-phase Checkpoint Is Intact In Atr-deficient Cmentioning

confidence: 99%

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation

2006

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“…The levels of Cdc25A protein are known to increase from the G1/S transition until mitosis (Bernardi et al, 2000;Molinari et al, 2000;Donzelli et al, 2002). In addition, Cdc25A overexpression induces unscheduled mitosis while its siRNA-mediated silencing causes a decrease in the percentage of mitotic cells (Molinari et al, 2000;Zhao et al, 2002).…”

Section: Cdc25a Function and Regulation In The Cell Cyclementioning

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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“…Its abundance is regulated by post-translational modification, which either stabilizes it or promotes its degradation (Mailand et al, 2002). Consequently, Cdc25A has two major peaks of accumulation during cell-cycle progression, one in G1 and the other in S/G2 (Bernardi et al, 2000).…”

Section: Cdc25a Phosphatasementioning

confidence: 99%

The Plk3-Cdc25 circuit

2005

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Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation

Cited by 66 publications

References 41 publications

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation

Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis

The Plk3-Cdc25 circuit

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