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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 exhibit extended survival and protection from thymic lymphomas(A) Kaplan-Meier survival plot comparing Atm+/+Wip1+/+ (N=55), Atm−/−Wip1+/+ (N=52), Atm−/−Wip1+/− (N=50), and Atm−/−Wip1−/− (N=43) mouse longevity. Atm−/−Wip1−/− mice are largely protected from developing thymic lymphomas and survive much longer than their Atm−/−Wip1+/+ and Atm−/−Wip1+/− counterparts (P = 2.42 × 10−14). (B-D) Representative hematoxylin and eosin stained sections of thymic lymphomas at 200X magnification from Atm−/−Wip1+/+ (B), Atm−/−Wip1+/− (C), and Atm−/−Wip1−/− (D) mice. No differences in histopathology were observed in the thymic lymphomas from Atm−/−Wip1−/− (N=3) mice when compared to Atm−/−Wip1+/+ (N=3) and Atm−/−Wip1+/− (N=3) littermates.
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Figure 1: Atm−/−Wip1−/− mice exhibit extended survival and protection from thymic lymphomas(A) Kaplan-Meier survival plot comparing Atm+/+Wip1+/+ (N=55), Atm−/−Wip1+/+ (N=52), Atm−/−Wip1+/− (N=50), and Atm−/−Wip1−/− (N=43) mouse longevity. Atm−/−Wip1−/− mice are largely protected from developing thymic lymphomas and survive much longer than their Atm−/−Wip1+/+ and Atm−/−Wip1+/− counterparts (P = 2.42 × 10−14). (B-D) Representative hematoxylin and eosin stained sections of thymic lymphomas at 200X magnification from Atm−/−Wip1+/+ (B), Atm−/−Wip1+/− (C), and Atm−/−Wip1−/− (D) mice. No differences in histopathology were observed in the thymic lymphomas from Atm−/−Wip1−/− (N=3) mice when compared to Atm−/−Wip1+/+ (N=3) and Atm−/−Wip1+/− (N=3) littermates.

Mentions: Atm mice succumb to thymic lymphomas at 3-6 months of age (Barlow et al., 1996; Elson et al., 1996; Xu et al., 1996; Westphal et al., 1997). Because WIP1 dephosphorylates some of the same targets that ATM phosphorylates, we hypothesized that the absence of Wip1 might rescue some of the deleterious phenotypes in the Atm mice. To test this hypothesis, Atm+/−Wip1+/+ mice were crossed to Atm+/+Wip1+/− mice, and double heterozygous F1 progeny were re-crossed to obtain F2 Atm+/+Wip1+/+, Atm−/−Wip1+/+, Atm−/−Wip1+/−, and Atm−/−Wip1−/− mice. A minimum of 43 mice for each genotype were monitored over their entire lifespan. As expected, Atm+/+Wip1+/+ mice live relatively normal lifespans of over two years (Fig. 1A). Consistent with previous reports, 95% of Atm−/−Wip1+/+ mice developed thymic lymphomas by 150 days of age, and all are dead by 300 days of age (Fig. 1A). Conversely, only 11% of Atm−/−Wip1−/− mice develop thymic lymphomas by 150 days of age, and rarely developed tumors after 180 days (6 months). The majority of the double knockout mice exhibited dramatically enhanced longevities compared to Atm mice, with median lifespans of 620 and 110 days, respectively (Fig. 1A). No Wip1 dosage effect was observed, as Atm−/−Wip1+/− mice developed tumors at the same rate as Atm−/−Wip1+/+ mice. Thus, the absence of Wip1 largely rescues tumor susceptibility phenotypes observed in 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 exhibit extended survival and protection from thymic lymphomas(A) Kaplan-Meier survival plot comparing Atm+/+Wip1+/+ (N=55), Atm−/−Wip1+/+ (N=52), Atm−/−Wip1+/− (N=50), and Atm−/−Wip1−/− (N=43) mouse longevity. Atm−/−Wip1−/− mice are largely protected from developing thymic lymphomas and survive much longer than their Atm−/−Wip1+/+ and Atm−/−Wip1+/− counterparts (P = 2.42 × 10−14). (B-D) Representative hematoxylin and eosin stained sections of thymic lymphomas at 200X magnification from Atm−/−Wip1+/+ (B), Atm−/−Wip1+/− (C), and Atm−/−Wip1−/− (D) mice. No differences in histopathology were observed in the thymic lymphomas from Atm−/−Wip1−/− (N=3) mice when compared to Atm−/−Wip1+/+ (N=3) and Atm−/−Wip1+/− (N=3) littermates.
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Figure 1: Atm−/−Wip1−/− mice exhibit extended survival and protection from thymic lymphomas(A) Kaplan-Meier survival plot comparing Atm+/+Wip1+/+ (N=55), Atm−/−Wip1+/+ (N=52), Atm−/−Wip1+/− (N=50), and Atm−/−Wip1−/− (N=43) mouse longevity. Atm−/−Wip1−/− mice are largely protected from developing thymic lymphomas and survive much longer than their Atm−/−Wip1+/+ and Atm−/−Wip1+/− counterparts (P = 2.42 × 10−14). (B-D) Representative hematoxylin and eosin stained sections of thymic lymphomas at 200X magnification from Atm−/−Wip1+/+ (B), Atm−/−Wip1+/− (C), and Atm−/−Wip1−/− (D) mice. No differences in histopathology were observed in the thymic lymphomas from Atm−/−Wip1−/− (N=3) mice when compared to Atm−/−Wip1+/+ (N=3) and Atm−/−Wip1+/− (N=3) littermates.
Mentions: Atm mice succumb to thymic lymphomas at 3-6 months of age (Barlow et al., 1996; Elson et al., 1996; Xu et al., 1996; Westphal et al., 1997). Because WIP1 dephosphorylates some of the same targets that ATM phosphorylates, we hypothesized that the absence of Wip1 might rescue some of the deleterious phenotypes in the Atm mice. To test this hypothesis, Atm+/−Wip1+/+ mice were crossed to Atm+/+Wip1+/− mice, and double heterozygous F1 progeny were re-crossed to obtain F2 Atm+/+Wip1+/+, Atm−/−Wip1+/+, Atm−/−Wip1+/−, and Atm−/−Wip1−/− mice. A minimum of 43 mice for each genotype were monitored over their entire lifespan. As expected, Atm+/+Wip1+/+ mice live relatively normal lifespans of over two years (Fig. 1A). Consistent with previous reports, 95% of Atm−/−Wip1+/+ mice developed thymic lymphomas by 150 days of age, and all are dead by 300 days of age (Fig. 1A). Conversely, only 11% of Atm−/−Wip1−/− mice develop thymic lymphomas by 150 days of age, and rarely developed tumors after 180 days (6 months). The majority of the double knockout mice exhibited dramatically enhanced longevities compared to Atm mice, with median lifespans of 620 and 110 days, respectively (Fig. 1A). No Wip1 dosage effect was observed, as Atm−/−Wip1+/− mice developed tumors at the same rate as Atm−/−Wip1+/+ mice. Thus, the absence of Wip1 largely rescues tumor susceptibility phenotypes observed in 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