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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 partial restoration of mature gamete formation(A-E) Representative hematoxylin and eosin (H&E) stained sections of testes from Atm+/+Wip1+/+ (N=4) (A), Atm+/+Wip1−/− (N=4) (B), Atm−/−Wip1+/+ (N=6) (C), and Atm−/−Wip1−/− (N=9) (D & E) mice at 200X magnification. Some testes from Atm−/−Wip1−/− mice show a partial rescue of spermatogenesis similar to that observed in testes from Atm+/+Wip1−/− mice. (F-J) H&E stained sections of ovaries from Atm+/+Wip1+/+ (N=4) (F), Atm+/+Wip1−/− (N=5) (G), Atm−/−Wip1+/+ (N=4) (H), and Atm−/−Wip1−/− (N=3) (I & J) mice at 40X magnification. Some Atm−/−Wip1−/− ovaries show a partial rescue of oogenesis similar to that observed in Atm+/+Wip1−/− ovaries.
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Figure 4: Atm−/−Wip1−/− mice exhibit partial restoration of mature gamete formation(A-E) Representative hematoxylin and eosin (H&E) stained sections of testes from Atm+/+Wip1+/+ (N=4) (A), Atm+/+Wip1−/− (N=4) (B), Atm−/−Wip1+/+ (N=6) (C), and Atm−/−Wip1−/− (N=9) (D & E) mice at 200X magnification. Some testes from Atm−/−Wip1−/− mice show a partial rescue of spermatogenesis similar to that observed in testes from Atm+/+Wip1−/− mice. (F-J) H&E stained sections of ovaries from Atm+/+Wip1+/+ (N=4) (F), Atm+/+Wip1−/− (N=5) (G), Atm−/−Wip1+/+ (N=4) (H), and Atm−/−Wip1−/− (N=3) (I & J) mice at 40X magnification. Some Atm−/−Wip1−/− ovaries show a partial rescue of oogenesis similar to that observed in Atm+/+Wip1−/− ovaries.

Mentions: Both A-T patients and Atm mice are infertile (Chun and Gatti, 2004). Testes and ovaries of Atm mice exhibit a disorganized architecture and complete absence of mature gametes (Barlow et al., 1996; Xu et al., 1996; Elson et al., 1996). To test if Atm−/−Wip1−/− mice were rescued from defects in gametogenesis, hematoxylin and eosin staining of tissue sections from testes and ovaries of Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− eight week old mice was performed. As expected, testes of Atm+/+Wip1+/+ males display a normal seminiferous tubule architecture (Fig. 4A). Testes of the Atm+/+Wip1−/− males revealed reduced numbers of maturing spermatocytes, spermatids, and mature sperm (Fig. 4B), as shown previously (Choi et al., 2002; Nannenga et al., 2006). Testes of Atm−/−Wip1+/+ males displayed diffuse hypoplasia of seminiferous tubules with multifocal degeneration of seminiferous tubule epithelium and no spermatogenesis (Fig. 4C). Interestingly, testes from four out of nine Atm−/−Wip1−/− males showed partial restoration of normal seminiferous tubule architecture and maturing spermatocytes, spermatids, and mature sperm similar to those seen in the Atm+/+Wip1−/− testes (Fig. 4D). The other five Atm−/−Wip1−/− males had complete disruption of seminiferous tubule organization and spermatogenesis, evidenced by the absence of spermatids and spermatozoa that was similar to the Atm testes (Fig. 4E).


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 partial restoration of mature gamete formation(A-E) Representative hematoxylin and eosin (H&E) stained sections of testes from Atm+/+Wip1+/+ (N=4) (A), Atm+/+Wip1−/− (N=4) (B), Atm−/−Wip1+/+ (N=6) (C), and Atm−/−Wip1−/− (N=9) (D & E) mice at 200X magnification. Some testes from Atm−/−Wip1−/− mice show a partial rescue of spermatogenesis similar to that observed in testes from Atm+/+Wip1−/− mice. (F-J) H&E stained sections of ovaries from Atm+/+Wip1+/+ (N=4) (F), Atm+/+Wip1−/− (N=5) (G), Atm−/−Wip1+/+ (N=4) (H), and Atm−/−Wip1−/− (N=3) (I & J) mice at 40X magnification. Some Atm−/−Wip1−/− ovaries show a partial rescue of oogenesis similar to that observed in Atm+/+Wip1−/− ovaries.
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Figure 4: Atm−/−Wip1−/− mice exhibit partial restoration of mature gamete formation(A-E) Representative hematoxylin and eosin (H&E) stained sections of testes from Atm+/+Wip1+/+ (N=4) (A), Atm+/+Wip1−/− (N=4) (B), Atm−/−Wip1+/+ (N=6) (C), and Atm−/−Wip1−/− (N=9) (D & E) mice at 200X magnification. Some testes from Atm−/−Wip1−/− mice show a partial rescue of spermatogenesis similar to that observed in testes from Atm+/+Wip1−/− mice. (F-J) H&E stained sections of ovaries from Atm+/+Wip1+/+ (N=4) (F), Atm+/+Wip1−/− (N=5) (G), Atm−/−Wip1+/+ (N=4) (H), and Atm−/−Wip1−/− (N=3) (I & J) mice at 40X magnification. Some Atm−/−Wip1−/− ovaries show a partial rescue of oogenesis similar to that observed in Atm+/+Wip1−/− ovaries.
Mentions: Both A-T patients and Atm mice are infertile (Chun and Gatti, 2004). Testes and ovaries of Atm mice exhibit a disorganized architecture and complete absence of mature gametes (Barlow et al., 1996; Xu et al., 1996; Elson et al., 1996). To test if Atm−/−Wip1−/− mice were rescued from defects in gametogenesis, hematoxylin and eosin staining of tissue sections from testes and ovaries of Atm+/+Wip1+/+, Atm+/+Wip1−/−, Atm−/−Wip1+/+, and Atm−/−Wip1−/− eight week old mice was performed. As expected, testes of Atm+/+Wip1+/+ males display a normal seminiferous tubule architecture (Fig. 4A). Testes of the Atm+/+Wip1−/− males revealed reduced numbers of maturing spermatocytes, spermatids, and mature sperm (Fig. 4B), as shown previously (Choi et al., 2002; Nannenga et al., 2006). Testes of Atm−/−Wip1+/+ males displayed diffuse hypoplasia of seminiferous tubules with multifocal degeneration of seminiferous tubule epithelium and no spermatogenesis (Fig. 4C). Interestingly, testes from four out of nine Atm−/−Wip1−/− males showed partial restoration of normal seminiferous tubule architecture and maturing spermatocytes, spermatids, and mature sperm similar to those seen in the Atm+/+Wip1−/− testes (Fig. 4D). The other five Atm−/−Wip1−/− males had complete disruption of seminiferous tubule organization and spermatogenesis, evidenced by the absence of spermatids and spermatozoa that was similar to the Atm testes (Fig. 4E).

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