A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis

Bahassi, El Mustapha; Yin, Moying; Robbins, Susan B.; Li, Yaqin; Conrady, Deborah G.; Yuan, Zhenyu; Kovall, Rhett A.; Herr, Andrew B.; Stambrook, Peter J.

doi:10.1186/1747-1028-6-4

Cited by 9 publications

(4 citation statements)

References 29 publications

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“…However, reduction in the level of Cdc25A was less severe when cells were transfected with ARD1 than when they were not ( Supplementary Figure S6A , lane 2 vs. 4). We next transfected cells with a Cdc25A-S82A mutant that is refractory to DNA damage-mediated degradation ( Supplementary Figure S6B , see lanes 5 and 6, used as control) [ 39 , 44 ], to ask whether depletion of ARD1, hence less acetylation, will allow some mutant Cdc25A degradation after etoposide administration. Surprisingly, ARD1A/B depletion led to reduced levels of wild-type and mutant Cdc25A-S82A ( Supplementary Figure S6B , compare lane 1 vs. 3, and 5 vs. 7).…”

Section: Resultsmentioning

confidence: 99%

Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer

et al. 2016

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The dual specificity phosphatase Cdc25A is a key regulator of the cell cycle that promotes cell cycle progression by dephosphorylating and activating cyclin-dependent kinases. In response to genotoxicants, Cdc25A undergoes posttranslational modifications which contribute to its proteasome-mediated degradation and consequent cell cycle checkpoint arrest. The most thoroughly studied Cdc25A modification is phosphorylation. We now provide the first evidence that Cdc25A can be acetylated and that it directly interacts with the ARD1 acetyltransferase which acetylates Cdc25A both biochemically and in cultured cells. When acetylated, Cdc25A has an extended half-life. We have also identified the class IV histone deacetylase, HDAC11, as a Cdc25A deacetylase. We further show that DNA damage, such as exposure to methyl methanesulfonate (MMS), etoposide or arsenic, increases Cdc25A acetylation. Importantly, this acetylation modulates Cdc25A phosphatase activity and its function as a cell cycle regulator, and may reflect a cellular response to DNA damage. Since Cdc25A, ARD1, and HDAC11 are frequently dysregulated in multiple types of cancer, our findings may provide insight into a novel mechanism in carcinogenesis.

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Section: Resultsmentioning

confidence: 99%

Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer

et al. 2016

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“…( 4 )). Consistently, in vivo studies showed that a human cancer-predisposing polymorphism, Cdc25A S88F, causes mouse embryonic lethality and induces apoptosis due to being incapable of binding to and inhibiting ASK1 [97], implying that the DSG motif might be critical for interaction between Cdc25A and ASK1. Furthermore, ectopic expression of Cdc25A was found to result in suppressing serum starvation-induced apoptosis by activating AKT [98].…”

Section: The Role Of Cdc25a In Apoptosismentioning

confidence: 93%

The Role of Cdc25A in the Regulation of Cell Proliferation and Apoptosis

Shen¹,

Huang²

2012

ACAMC

165

143

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Cell division cycle 25 A (Cdc25A), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (CDKs), such as CDK2, CDK4, and CDK6, and positively regulates the activities of CDKs that lead to cell cycle progression. In addition, Cdc25A also acts as a regulator of apoptosis. Overexpression of Cdc25A promotes tumorigenesis, and is frequently observed in various types of cancer. Here we briefly summarize current understanding of the role of Cdc25A in cell proliferation and apoptosis, as well as the impact of overexpression of Cdc25A on tumorigenesis.

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“…RPE-1- TP53 wt and RPE-1- TP53 mut cell lines were engineered to express Cdc25A or Cyclin E1 in a doxycycline-dependent manner. To this end, human CDC25A was PCR amplified from FLAG-CDC25A-WT, which was a gift from Peter Stambrook 55 , using the following oligos: forward: 5′-CGCGGCCGCCATGGAACTGGGCCCGGAGCCC-3′, reverse: 5′-GATGAATTCTCACAGCTTCTTCAGACG-3′. Human CCNE1 was PCR amplified from Rc-CycE, which was a gift from Bob Weinberg (Plasmid #8963, Addgene) 56 , using the following oligos: forward: 5′-CGCGGCCGCCATGAAGGAGGACGGCGGCGCG-3′, reverse: 5′-GATGAATTCTCACGCCATTTCCGGCCC-3′.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

et al. 2020

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Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases. We modeled oncogene-induced replication stress using inducible expression of Cyclin E1 or Cdc25A in non-transformed RPE-1 cells, either in a TP53 wild-type or TP53-mutant background. DNA fiber analysis showed Cyclin E1 or Cdc25A overexpression to slow replication speed. The resulting replication-derived DNA lesions were transmitted into mitosis causing chromosome segregation defects. Single cell sequencing revealed that replication stress and mitotic defects upon Cyclin E1 or Cdc25A overexpression resulted in genomic instability. ATR or WEE1 inhibition exacerbated the mitotic aberrancies induced by Cyclin E1 or Cdc25A overexpression, and caused cytotoxicity. Both these phenotypes were exacerbated upon p53 inactivation. Conversely, downregulation of Cyclin E1 rescued both replication kinetics, as well as sensitivity to ATR and WEE1 inhibitors. Taken together, Cyclin E1 or Cdc25A-induced replication stress leads to mitotic segregation defects and genomic instability. These mitotic defects are exacerbated by inhibition of ATR or WEE1 and therefore point to mitotic catastrophe as an underlying mechanism. Importantly, our data suggest that Cyclin E1 overexpression can be used to select patients for treatment with replication checkpoint inhibitors.

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A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis

Cited by 9 publications

References 29 publications

Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer

Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer

The Role of Cdc25A in the Regulation of Cell Proliferation and Apoptosis

Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors

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