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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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Model showing how Wip1 may compensate for Atm deficiency to partially rescue A-T-associated tumor phenotypes(A) In Atm+/+Wip1+/+ animals, DNA damage activates Atm, which phosphorylates many targets, including p53, to activate the DNA damage response and prevent genomic instability. Normal Wip1 activity then modulates and reduces phosphorylation of p53 and other Atm targets. This overall robust DNA damage response protects against tumor formation. (B) In Atm+/+Wip1−/− animals, phosphorylation of Atm targets is increased by absence of Wip1, resulting in an augmented DNA damage response, enhanced genomic stability, and virtually no tumors. (C) In Atm−/−Wip1+/+ animals, phosphorylation of Atm targets is decreased and only partially compensated by other PIKKs such as Atr and DNA-PK, resulting in genomic instability and a high rate of cancers. (D) In Atm−/−Wip1−/− animals, compensatory phosphorylation of Atm targets by Atr and DNA-PK is increased and prolonged by absence of Wip1, allowing for an enhanced DNA damage response, partial restoration of genomic stability, and fewer tumors than in the Atm−/−Wip1+/+ animals.
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Figure 7: Model showing how Wip1 may compensate for Atm deficiency to partially rescue A-T-associated tumor phenotypes(A) In Atm+/+Wip1+/+ animals, DNA damage activates Atm, which phosphorylates many targets, including p53, to activate the DNA damage response and prevent genomic instability. Normal Wip1 activity then modulates and reduces phosphorylation of p53 and other Atm targets. This overall robust DNA damage response protects against tumor formation. (B) In Atm+/+Wip1−/− animals, phosphorylation of Atm targets is increased by absence of Wip1, resulting in an augmented DNA damage response, enhanced genomic stability, and virtually no tumors. (C) In Atm−/−Wip1+/+ animals, phosphorylation of Atm targets is decreased and only partially compensated by other PIKKs such as Atr and DNA-PK, resulting in genomic instability and a high rate of cancers. (D) In Atm−/−Wip1−/− animals, compensatory phosphorylation of Atm targets by Atr and DNA-PK is increased and prolonged by absence of Wip1, allowing for an enhanced DNA damage response, partial restoration of genomic stability, and fewer tumors than in the Atm−/−Wip1+/+ animals.

Mentions: WIP1 dephosphorylates many of the same targets that ATM phosphorylates (Lu et al., 2008; Le and Bulavin, 2009). In addition, Shreeram et al. (2006a) have demonstrated that Wip1 directly desphorylates ATM at Ser1981 and is critical for resetting ATM phosphorylation as cells repaired damaged DNA. Because of this antagonistic relationship between ATM and WIP1, we hypothesized that mice lacking Atm, which exhibit many deleterious phenotypes, might benefit from the absence of Wip1. Our hypothesized mechanism for Wip1 rescue was that, despite some compensatory phosphorylation by other PIKKs such as Atr and DNA-PK, many Atm targets would be hypophosphorylated in the absence of Atm. Therefore, the absence of Wip1 would likely increase and prolong the phosphorylation state of hypophosphorylated Atm targets, ultimately restoring a more normal DNA damage response (Fig. 7). If Wip1 absence or inhibition could benefit Atm mice, this could have important implications for A-T patients, as there is currently no effective treatment for these individuals. WIP1 small molecule inhibitors have recently been developed as potential cancer therapeutic drugs (Yamaguchi et al., 2006; Belova et al., 2005; Rayter et al., 2008), so it is possible such drugs might alleviate some A-T patient symptoms.


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)

Model showing how Wip1 may compensate for Atm deficiency to partially rescue A-T-associated tumor phenotypes(A) In Atm+/+Wip1+/+ animals, DNA damage activates Atm, which phosphorylates many targets, including p53, to activate the DNA damage response and prevent genomic instability. Normal Wip1 activity then modulates and reduces phosphorylation of p53 and other Atm targets. This overall robust DNA damage response protects against tumor formation. (B) In Atm+/+Wip1−/− animals, phosphorylation of Atm targets is increased by absence of Wip1, resulting in an augmented DNA damage response, enhanced genomic stability, and virtually no tumors. (C) In Atm−/−Wip1+/+ animals, phosphorylation of Atm targets is decreased and only partially compensated by other PIKKs such as Atr and DNA-PK, resulting in genomic instability and a high rate of cancers. (D) In Atm−/−Wip1−/− animals, compensatory phosphorylation of Atm targets by Atr and DNA-PK is increased and prolonged by absence of Wip1, allowing for an enhanced DNA damage response, partial restoration of genomic stability, and fewer tumors than in the Atm−/−Wip1+/+ animals.
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Related In: Results  -  Collection

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Figure 7: Model showing how Wip1 may compensate for Atm deficiency to partially rescue A-T-associated tumor phenotypes(A) In Atm+/+Wip1+/+ animals, DNA damage activates Atm, which phosphorylates many targets, including p53, to activate the DNA damage response and prevent genomic instability. Normal Wip1 activity then modulates and reduces phosphorylation of p53 and other Atm targets. This overall robust DNA damage response protects against tumor formation. (B) In Atm+/+Wip1−/− animals, phosphorylation of Atm targets is increased by absence of Wip1, resulting in an augmented DNA damage response, enhanced genomic stability, and virtually no tumors. (C) In Atm−/−Wip1+/+ animals, phosphorylation of Atm targets is decreased and only partially compensated by other PIKKs such as Atr and DNA-PK, resulting in genomic instability and a high rate of cancers. (D) In Atm−/−Wip1−/− animals, compensatory phosphorylation of Atm targets by Atr and DNA-PK is increased and prolonged by absence of Wip1, allowing for an enhanced DNA damage response, partial restoration of genomic stability, and fewer tumors than in the Atm−/−Wip1+/+ animals.
Mentions: WIP1 dephosphorylates many of the same targets that ATM phosphorylates (Lu et al., 2008; Le and Bulavin, 2009). In addition, Shreeram et al. (2006a) have demonstrated that Wip1 directly desphorylates ATM at Ser1981 and is critical for resetting ATM phosphorylation as cells repaired damaged DNA. Because of this antagonistic relationship between ATM and WIP1, we hypothesized that mice lacking Atm, which exhibit many deleterious phenotypes, might benefit from the absence of Wip1. Our hypothesized mechanism for Wip1 rescue was that, despite some compensatory phosphorylation by other PIKKs such as Atr and DNA-PK, many Atm targets would be hypophosphorylated in the absence of Atm. Therefore, the absence of Wip1 would likely increase and prolong the phosphorylation state of hypophosphorylated Atm targets, ultimately restoring a more normal DNA damage response (Fig. 7). If Wip1 absence or inhibition could benefit Atm mice, this could have important implications for A-T patients, as there is currently no effective treatment for these individuals. WIP1 small molecule inhibitors have recently been developed as potential cancer therapeutic drugs (Yamaguchi et al., 2006; Belova et al., 2005; Rayter et al., 2008), so it is possible such drugs might alleviate some A-T patient symptoms.

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