Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase

The ataxia telangiectasia mutated (ATM) kinase is a key tumor suppressor that regulates numerous cell cycle checkpoints as well as apoptosis. Here, we report that ATM is a critical player in the regulation of apoptosis and lymphomagenesis in the presence of c-myc. In turn, deletion of the inhibitory ATM phosphatase, Wip1, results in ATM up-regulation and suppression of Eμ-myc–induced B cell lymphomas. Using mouse genetic crosses, we show that the onset of myc-induced lymphomas is dramatically delayed in Wip1-null mice in an ATM- and p53-, but not p38 MAPK– or Arf-, dependent manner. We propose that Wip1 phosphatase is critical for regulating the ATM-mediated tumor surveillance network.

[1]  Francis Collins,et al.  Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia , 1996, Cell.

[2]  Albert J. Fornace,et al.  Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity , 2002, Nature Genetics.

[3]  Jeffrey R. Marks,et al.  Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23 , 2002, Nature Genetics.

[4]  E. Hölttä,et al.  Caspases and mitochondria in c-Myc-induced apoptosis: identification of ATM as a new target of caspases , 2000, Oncogene.

[5]  M. Lavin,et al.  Involvement of novel autophosphorylation sites in ATM activation , 2006, The EMBO journal.

[6]  L. Donehower,et al.  PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. , 2005, Genes & development.

[7]  Dahai Zhu,et al.  ATM activity contributes to the tumor-suppressing functions of p14ARF , 2004, Oncogene.

[8]  K. Khanna,et al.  Autophosphorylation of ataxia‐telangiectasia mutated is regulated by protein phosphatase 2A , 2004, The EMBO journal.

[9]  S. Jackson,et al.  Cleavage and Inactivation of ATM during Apoptosis , 1999, Molecular and Cellular Biology.

[10]  T. Ørntoft,et al.  DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis , 2005, Nature.

[11]  R. Palmiter,et al.  The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice , 1985, Nature.

[12]  E. Appella,et al.  Wip1 phosphatase modulates ATM-dependent signaling pathways. , 2006, Molecular cell.

[13]  S. Lowe,et al.  INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. , 1999, Genes & development.

[14]  L. Donehower,et al.  Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway , 2004, Nature Genetics.

[15]  Jiri Bartek,et al.  Cell-cycle checkpoints and cancer , 2004, Nature.

[16]  Y. Shiloh,et al.  ATM: genome stability, neuronal development, and cancer cross paths. , 2001, Advances in cancer research.

[17]  John T. Powers,et al.  E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. , 2004, Molecular cancer research : MCR.

[18]  E. Brambilla,et al.  p14ARF Activates a Tip60-Dependent and p53-Independent ATM/ATR/CHK Pathway in Response to Genotoxic Stress , 2006, Molecular and Cellular Biology.

[19]  P. Bouillet,et al.  Bim is a suppressor of Myc-induced mouse B cell leukemia. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[20]  N. Gueven,et al.  ATP Activates Ataxia-Telangiectasia Mutated (ATM) in Vitro , 2003, The Journal of Biological Chemistry.

[21]  Michel C. Nussenzweig,et al.  Role of genomic instability and p53 in AID-induced c-myc–Igh translocations , 2006, Nature.

[22]  Masaaki Adachi,et al.  p53‐inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK‐p53 signaling in response to UV radiation , 2000, The EMBO journal.

[23]  S. Durell,et al.  Substrate Specificity of the Human Protein Phosphatase 2Cδ, Wip1† , 2005 .

[24]  N. Onishi,et al.  Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase , 2006, Cell Death and Differentiation.

[25]  A. Nussenzweig,et al.  Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo , 2006, Nature.

[26]  M. Roussel,et al.  Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. , 1999, Genes & development.