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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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Absence of Wip1 does not rescue somatic growth, motor coordination defects, or immunologic abnormalities in Atm  mice(A) Absence of Wip1 does not rescue somatic growth. Male and female Atm+/+Wip1+/+ (N=16 males, 8 females), Atm+/+Wip1−/− (N=10 males, 7 females), Atm−/−Wip1+/+ (N=9 males, 13 females), and Atm−/−Wip1−/− (N=7 males, 11 females) mice were weighed at 8 weeks of age. Atm−/−Wip1+/+ and Atm−/−Wip1−/− males and females exhibited a significantly reduced bodyweight compared to Atm+/+Wip1+/+ mice. (B) Absence of Wip1 does not rescue motor coordination defects. Using the rota-rod treadmill test, Atm−/−Wip1+/+ (N=12) and Atm−/−Wip1−/− (N=10) mice exhibit significant motor coordination defects compared to their Atm+/+Wip1+/+ (N=12) and Atm+/+Wip1−/− (N=14) counterparts. (C) Absence of Wip1 does not rescue lymphoid cell depletion. Thymocytes and splenocytes were collected from Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− mice at 8 weeks of age, (N=10 for all genotypes) and counted. The Atm−/−Wip1−/− mice have significantly decreased numbers of both splenocytes and thymocytes compared to Atm+/+Wip1+/+ mice but not compared to Atm−/−Wip1+/+ mice. (D) Absence of Wip1 does not rescue defective thymocyte maturation. Thymocytes were collected from Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− mice at 8 weeks of age, (N=10 for all genotypes). Thymocyte expression of CD3, CD4, and CD8 was examined using flow cytometry. Atm−/−Wip1−/− thymocytes show a decrease in mature T cells similar to Atm−/−Wip1+/+ thymocytes. Also, both Atm−/−Wip1+/+ and Atm−/−Wip1−/− thymocytes show a decrease in the CD4 single positive population compared to Atm+/+Wip1+/+. Asterisks in panels A, C, and D represent a significant difference between the indicated population and the control Atm+/+Wip1+/+ mice as measured by t test. *P < 0.05 and **P < 0.01.
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Figure 6: Absence of Wip1 does not rescue somatic growth, motor coordination defects, or immunologic abnormalities in Atm mice(A) Absence of Wip1 does not rescue somatic growth. Male and female Atm+/+Wip1+/+ (N=16 males, 8 females), Atm+/+Wip1−/− (N=10 males, 7 females), Atm−/−Wip1+/+ (N=9 males, 13 females), and Atm−/−Wip1−/− (N=7 males, 11 females) mice were weighed at 8 weeks of age. Atm−/−Wip1+/+ and Atm−/−Wip1−/− males and females exhibited a significantly reduced bodyweight compared to Atm+/+Wip1+/+ mice. (B) Absence of Wip1 does not rescue motor coordination defects. Using the rota-rod treadmill test, Atm−/−Wip1+/+ (N=12) and Atm−/−Wip1−/− (N=10) mice exhibit significant motor coordination defects compared to their Atm+/+Wip1+/+ (N=12) and Atm+/+Wip1−/− (N=14) counterparts. (C) Absence of Wip1 does not rescue lymphoid cell depletion. Thymocytes and splenocytes were collected from Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− mice at 8 weeks of age, (N=10 for all genotypes) and counted. The Atm−/−Wip1−/− mice have significantly decreased numbers of both splenocytes and thymocytes compared to Atm+/+Wip1+/+ mice but not compared to Atm−/−Wip1+/+ mice. (D) Absence of Wip1 does not rescue defective thymocyte maturation. Thymocytes were collected from Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− mice at 8 weeks of age, (N=10 for all genotypes). Thymocyte expression of CD3, CD4, and CD8 was examined using flow cytometry. Atm−/−Wip1−/− thymocytes show a decrease in mature T cells similar to Atm−/−Wip1+/+ thymocytes. Also, both Atm−/−Wip1+/+ and Atm−/−Wip1−/− thymocytes show a decrease in the CD4 single positive population compared to Atm+/+Wip1+/+. Asterisks in panels A, C, and D represent a significant difference between the indicated population and the control Atm+/+Wip1+/+ mice as measured by t test. *P < 0.05 and **P < 0.01.

Mentions: Several other Atm deficiency phenotypes were tested for rescue by the absence of Wip1. These included adult body mass (reduced in Atm mice), motor coordination (reduced in Atm mice), lymphocyte numbers (reduced in Atm mice), and T cell maturation (defective in Atm mice). As shown in Figure 6, Atm−/−Wip1−/− mice were comparable to Atm−/− mice in mean body mass at 8 weeks of age (Fig. 6A), length of time maintaining balance on a spinning rota rod (a test of motor coordination) (Fig. 6B), total splenocyte and thymocyte numbers (Fig. 6C), and numbers of CD4+ CD8+ double positive (higher numbers in Atm mice are indicative of defective T cell maturation) and single positive CD4+ thymic T lymphocytes (Fig. 6D). Thus, not all phenotypes associated with Atm deficiency could be rescued or partially rescued by the absence of Wip1.


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)

Absence of Wip1 does not rescue somatic growth, motor coordination defects, or immunologic abnormalities in Atm  mice(A) Absence of Wip1 does not rescue somatic growth. Male and female Atm+/+Wip1+/+ (N=16 males, 8 females), Atm+/+Wip1−/− (N=10 males, 7 females), Atm−/−Wip1+/+ (N=9 males, 13 females), and Atm−/−Wip1−/− (N=7 males, 11 females) mice were weighed at 8 weeks of age. Atm−/−Wip1+/+ and Atm−/−Wip1−/− males and females exhibited a significantly reduced bodyweight compared to Atm+/+Wip1+/+ mice. (B) Absence of Wip1 does not rescue motor coordination defects. Using the rota-rod treadmill test, Atm−/−Wip1+/+ (N=12) and Atm−/−Wip1−/− (N=10) mice exhibit significant motor coordination defects compared to their Atm+/+Wip1+/+ (N=12) and Atm+/+Wip1−/− (N=14) counterparts. (C) Absence of Wip1 does not rescue lymphoid cell depletion. Thymocytes and splenocytes were collected from Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− mice at 8 weeks of age, (N=10 for all genotypes) and counted. The Atm−/−Wip1−/− mice have significantly decreased numbers of both splenocytes and thymocytes compared to Atm+/+Wip1+/+ mice but not compared to Atm−/−Wip1+/+ mice. (D) Absence of Wip1 does not rescue defective thymocyte maturation. Thymocytes were collected from Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− mice at 8 weeks of age, (N=10 for all genotypes). Thymocyte expression of CD3, CD4, and CD8 was examined using flow cytometry. Atm−/−Wip1−/− thymocytes show a decrease in mature T cells similar to Atm−/−Wip1+/+ thymocytes. Also, both Atm−/−Wip1+/+ and Atm−/−Wip1−/− thymocytes show a decrease in the CD4 single positive population compared to Atm+/+Wip1+/+. Asterisks in panels A, C, and D represent a significant difference between the indicated population and the control Atm+/+Wip1+/+ mice as measured by t test. *P < 0.05 and **P < 0.01.
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Figure 6: Absence of Wip1 does not rescue somatic growth, motor coordination defects, or immunologic abnormalities in Atm mice(A) Absence of Wip1 does not rescue somatic growth. Male and female Atm+/+Wip1+/+ (N=16 males, 8 females), Atm+/+Wip1−/− (N=10 males, 7 females), Atm−/−Wip1+/+ (N=9 males, 13 females), and Atm−/−Wip1−/− (N=7 males, 11 females) mice were weighed at 8 weeks of age. Atm−/−Wip1+/+ and Atm−/−Wip1−/− males and females exhibited a significantly reduced bodyweight compared to Atm+/+Wip1+/+ mice. (B) Absence of Wip1 does not rescue motor coordination defects. Using the rota-rod treadmill test, Atm−/−Wip1+/+ (N=12) and Atm−/−Wip1−/− (N=10) mice exhibit significant motor coordination defects compared to their Atm+/+Wip1+/+ (N=12) and Atm+/+Wip1−/− (N=14) counterparts. (C) Absence of Wip1 does not rescue lymphoid cell depletion. Thymocytes and splenocytes were collected from Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− mice at 8 weeks of age, (N=10 for all genotypes) and counted. The Atm−/−Wip1−/− mice have significantly decreased numbers of both splenocytes and thymocytes compared to Atm+/+Wip1+/+ mice but not compared to Atm−/−Wip1+/+ mice. (D) Absence of Wip1 does not rescue defective thymocyte maturation. Thymocytes were collected from Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− mice at 8 weeks of age, (N=10 for all genotypes). Thymocyte expression of CD3, CD4, and CD8 was examined using flow cytometry. Atm−/−Wip1−/− thymocytes show a decrease in mature T cells similar to Atm−/−Wip1+/+ thymocytes. Also, both Atm−/−Wip1+/+ and Atm−/−Wip1−/− thymocytes show a decrease in the CD4 single positive population compared to Atm+/+Wip1+/+. Asterisks in panels A, C, and D represent a significant difference between the indicated population and the control Atm+/+Wip1+/+ mice as measured by t test. *P < 0.05 and **P < 0.01.
Mentions: Several other Atm deficiency phenotypes were tested for rescue by the absence of Wip1. These included adult body mass (reduced in Atm mice), motor coordination (reduced in Atm mice), lymphocyte numbers (reduced in Atm mice), and T cell maturation (defective in Atm mice). As shown in Figure 6, Atm−/−Wip1−/− mice were comparable to Atm−/− mice in mean body mass at 8 weeks of age (Fig. 6A), length of time maintaining balance on a spinning rota rod (a test of motor coordination) (Fig. 6B), total splenocyte and thymocyte numbers (Fig. 6C), and numbers of CD4+ CD8+ double positive (higher numbers in Atm mice are indicative of defective T cell maturation) and single positive CD4+ thymic T lymphocytes (Fig. 6D). Thus, not all phenotypes associated with Atm deficiency could be rescued or partially rescued by the absence of Wip1.

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