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Absence of Wip1 partially rescues Atm deficiency phenotypes in mice.

Darlington Y, Nguyen TA, Moon SH, Herron A, Rao P, Zhu C, Lu X, Donehower LA - Oncogene (2011)

Bottom Line: WIP1 may have a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair.Additionally, double knockout splenocytes displayed reduced chromosomal instability compared with Atm mice.These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Graduate Program in Cell and Molecular Biology, Houston, Baylor College of Medicine, Houston, TX 77030, USA.

ABSTRACT
Wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may have a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossed Atm-deficient mice to Wip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes. Atm mice, like ATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared with Atm mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared with their Atm counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared with Atm mice. Finally, doubly mice were partially rescued from gametogenesis defects observed in Atm mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular.

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Atm−/−Wip1−/− mice are more sensitive to IR than Atm−/−Wip1+/+ mice(A) Survival plot comparing survival of Atm+/+Wip1+/+ (N=4), Atm+/+Wip1−/− (N=6), Atm−/−Wip1+/+ (N=5), and Atm−/−Wip1−/− (N=7) mice after whole body IR with 8 Gy. Atm−/−Wip1+/+ and Atm−/−Wip1−/− mice are more sensitive to IR compared to Atm+/+Wip1+/+ mice. This difference approached significance (P = 0.06). (B) Survival plot comparing survival of Atm+/+Wip1+/+ (N=5), Atm+/+Wip1−/− (N=6), Atm−/−Wip1+/+ (N=10), and Atm−/−Wip1−/− (N=11) mice after whole body IR with 4 Gy. Atm−/−Wip1−/− mice are significantly more sensitive to IR compared to their Atm−/−Wip1+/+ counterparts (P = 0.002). (C) Representative H&E stained sections of small intestines of Atm+/+Wip1+/+ (N=3), Atm+/+Wip1−/− (N=3), Atm−/−Wip1+/+ (N=3), and Atm−/−Wip1−/− (N=3) mice after whole body IR with 4 Gy or unirradiated and collected 2, 3, and 4 days after treatment. The small intestines of the Atm−/−Wip1−/− mice display an enhanced radiation toxicity phenotype compared to other genotypes.
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Figure 5: Atm−/−Wip1−/− mice are more sensitive to IR than Atm−/−Wip1+/+ mice(A) Survival plot comparing survival of Atm+/+Wip1+/+ (N=4), Atm+/+Wip1−/− (N=6), Atm−/−Wip1+/+ (N=5), and Atm−/−Wip1−/− (N=7) mice after whole body IR with 8 Gy. Atm−/−Wip1+/+ and Atm−/−Wip1−/− mice are more sensitive to IR compared to Atm+/+Wip1+/+ mice. This difference approached significance (P = 0.06). (B) Survival plot comparing survival of Atm+/+Wip1+/+ (N=5), Atm+/+Wip1−/− (N=6), Atm−/−Wip1+/+ (N=10), and Atm−/−Wip1−/− (N=11) mice after whole body IR with 4 Gy. Atm−/−Wip1−/− mice are significantly more sensitive to IR compared to their Atm−/−Wip1+/+ counterparts (P = 0.002). (C) Representative H&E stained sections of small intestines of Atm+/+Wip1+/+ (N=3), Atm+/+Wip1−/− (N=3), Atm−/−Wip1+/+ (N=3), and Atm−/−Wip1−/− (N=3) mice after whole body IR with 4 Gy or unirradiated and collected 2, 3, and 4 days after treatment. The small intestines of the Atm−/−Wip1−/− mice display an enhanced radiation toxicity phenotype compared to other genotypes.

Mentions: Both A-T patients and Atm mice are hypersensitive to IR (Westphal et al., 1997; Barlow et al., 1996; Chun and Gatti, 2004). To test if Atm−/−Wip1−/− mice were rescued from this phenotype, Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− six week old mice were subjected to a lethal dose of 8 Gy IR and monitored for survival. Atm+/+Wip1+/+ mice died between days 13-30 after IR (Fig. 5A). Atm+/+Wip1−/− mice died between days 11-17 after IR, suggesting a slightly enhanced sensitivity to IR compared to their wildtype counterparts. As anticipated, Atm−/−Wip1+/+ mice died more rapidly, between days 4-16. Likewise, Atm−/−Wip1−/− mice died between days 4-10 after IR. Thus, at the 8 Gy dosage, Atm−/−Wip1−/− mice were not rescued from the IR hypersensitivity phenotype of Atm mice. We used a normally sublethal dosage of 4 Gy IR to determine if there were IR sensitivity differences among Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− six week old mice. All Atm+/+Wip1+/+, Atm+/+Wip1−/−, and Atm−/−Wip1+/+ mice were monitored for 50 days, and all survived 4 Gy treatment (Fig. 5B). However, 7 of 11 (64%) of the Atm−/−Wip1−/− mice died between days 14 and 30 after 4 Gy IR (Fig. 5B). Thus, rather than rescue IR hypersensitivity, absence of Wip1 further increases the IR sensitivity of Atm mice.


Absence of Wip1 partially rescues Atm deficiency phenotypes in mice.

Darlington Y, Nguyen TA, Moon SH, Herron A, Rao P, Zhu C, Lu X, Donehower LA - Oncogene (2011)

Atm−/−Wip1−/− mice are more sensitive to IR than Atm−/−Wip1+/+ mice(A) Survival plot comparing survival of Atm+/+Wip1+/+ (N=4), Atm+/+Wip1−/− (N=6), Atm−/−Wip1+/+ (N=5), and Atm−/−Wip1−/− (N=7) mice after whole body IR with 8 Gy. Atm−/−Wip1+/+ and Atm−/−Wip1−/− mice are more sensitive to IR compared to Atm+/+Wip1+/+ mice. This difference approached significance (P = 0.06). (B) Survival plot comparing survival of Atm+/+Wip1+/+ (N=5), Atm+/+Wip1−/− (N=6), Atm−/−Wip1+/+ (N=10), and Atm−/−Wip1−/− (N=11) mice after whole body IR with 4 Gy. Atm−/−Wip1−/− mice are significantly more sensitive to IR compared to their Atm−/−Wip1+/+ counterparts (P = 0.002). (C) Representative H&E stained sections of small intestines of Atm+/+Wip1+/+ (N=3), Atm+/+Wip1−/− (N=3), Atm−/−Wip1+/+ (N=3), and Atm−/−Wip1−/− (N=3) mice after whole body IR with 4 Gy or unirradiated and collected 2, 3, and 4 days after treatment. The small intestines of the Atm−/−Wip1−/− mice display an enhanced radiation toxicity phenotype compared to other genotypes.
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Figure 5: Atm−/−Wip1−/− mice are more sensitive to IR than Atm−/−Wip1+/+ mice(A) Survival plot comparing survival of Atm+/+Wip1+/+ (N=4), Atm+/+Wip1−/− (N=6), Atm−/−Wip1+/+ (N=5), and Atm−/−Wip1−/− (N=7) mice after whole body IR with 8 Gy. Atm−/−Wip1+/+ and Atm−/−Wip1−/− mice are more sensitive to IR compared to Atm+/+Wip1+/+ mice. This difference approached significance (P = 0.06). (B) Survival plot comparing survival of Atm+/+Wip1+/+ (N=5), Atm+/+Wip1−/− (N=6), Atm−/−Wip1+/+ (N=10), and Atm−/−Wip1−/− (N=11) mice after whole body IR with 4 Gy. Atm−/−Wip1−/− mice are significantly more sensitive to IR compared to their Atm−/−Wip1+/+ counterparts (P = 0.002). (C) Representative H&E stained sections of small intestines of Atm+/+Wip1+/+ (N=3), Atm+/+Wip1−/− (N=3), Atm−/−Wip1+/+ (N=3), and Atm−/−Wip1−/− (N=3) mice after whole body IR with 4 Gy or unirradiated and collected 2, 3, and 4 days after treatment. The small intestines of the Atm−/−Wip1−/− mice display an enhanced radiation toxicity phenotype compared to other genotypes.
Mentions: Both A-T patients and Atm mice are hypersensitive to IR (Westphal et al., 1997; Barlow et al., 1996; Chun and Gatti, 2004). To test if Atm−/−Wip1−/− mice were rescued from this phenotype, Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− six week old mice were subjected to a lethal dose of 8 Gy IR and monitored for survival. Atm+/+Wip1+/+ mice died between days 13-30 after IR (Fig. 5A). Atm+/+Wip1−/− mice died between days 11-17 after IR, suggesting a slightly enhanced sensitivity to IR compared to their wildtype counterparts. As anticipated, Atm−/−Wip1+/+ mice died more rapidly, between days 4-16. Likewise, Atm−/−Wip1−/− mice died between days 4-10 after IR. Thus, at the 8 Gy dosage, Atm−/−Wip1−/− mice were not rescued from the IR hypersensitivity phenotype of Atm mice. We used a normally sublethal dosage of 4 Gy IR to determine if there were IR sensitivity differences among Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− six week old mice. All Atm+/+Wip1+/+, Atm+/+Wip1−/−, and Atm−/−Wip1+/+ mice were monitored for 50 days, and all survived 4 Gy treatment (Fig. 5B). However, 7 of 11 (64%) of the Atm−/−Wip1−/− mice died between days 14 and 30 after 4 Gy IR (Fig. 5B). Thus, rather than rescue IR hypersensitivity, absence of Wip1 further increases the IR sensitivity of Atm mice.

Bottom Line: WIP1 may have a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair.Additionally, double knockout splenocytes displayed reduced chromosomal instability compared with Atm mice.These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Graduate Program in Cell and Molecular Biology, Houston, Baylor College of Medicine, Houston, TX 77030, USA.

ABSTRACT
Wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may have a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossed Atm-deficient mice to Wip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes. Atm mice, like ATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared with Atm mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared with their Atm counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared with Atm mice. Finally, doubly mice were partially rescued from gametogenesis defects observed in Atm mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular.

Show MeSH
Related in: MedlinePlus