Mutations in the p53 and SCID genes cooperate in tumorigenesis.

DNA damage can cause mutations that contribute to cellular transformation and tumorigenesis. The p53 tumor suppressor acts to protect the organism from DNA damage by inducing either G1 arrest to facilitate DNA repair or by activating physiological cell death (apoptosis). Consistent with this critical function of p53, mice lacking p53 are predisposed to developing tumors, particularly lymphoma. The severe combined immune deficiency (scid) focus encodes the catalytic subunit of DNA protein kinase (DNA-PKcs), a protein complex that has a role in the cellular response to DNA damage. Cells from scid mice are hypersensitive to radiation and scid lymphocytes fail to develop from precursors because they are unable to properly join DNA-coding ends during antigen receptor gene rearrangement. We examined the combined effect of loss of p53 and loss of DNA-PKcs on lymphocyte development and tumorigenesis by generating p53-/- scid mice. Our data demonstrate that loss of p53 promotes T-cell development in scid mice but does not noticeably affect B lymphopoiesis. Moreover, scid cells are able to induce p53 protein expression and activate G1 arrest or apoptosis in response to ionizing radiation, indicating that DNA-PKcs is not essential for these responses to DNA damage. Furthermore, p53-/- scid double mutant mice develop lymphoma earlier than p53-/- littermates, demonstrating that loss of these two genes can cooperate in tumorigenesis. Collectively, these results provide evidence for an unsuspected role of p53 as a checkpoint regulator in early T-cell development and demonstrate that loss of an additional component of the cellular response to DNA damage can cooperate with loss of p53 in lymphomagenesis.

[1]  L. Donehower,et al.  p53 is required for both radiation-induced differentiation and rescue of V(D)J rearrangement in scid mouse thymocytes. , 1996, Genes & development.

[2]  D. Weaver,et al.  What to do at an end: DNA double-strand-break repair. , 1995, Trends in genetics : TIG.

[3]  G. Stark,et al.  p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Guillouf,et al.  p53 involvement in control of G2 exit of the cell cycle: role in DNA damage-induced apoptosis. , 1995, Oncogene.

[5]  S. Friend,et al.  Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. , 1995, Cancer research.

[6]  F. Alt,et al.  Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation , 1995, Cell.

[7]  J. Danska,et al.  Development of CD4+CD8+ thymocytes in RAG-deficient mice through a T cell receptor beta chain-independent pathway , 1995, The Journal of experimental medicine.

[8]  D. Chan,et al.  Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line , 1995, Science.

[9]  M. Oettinger,et al.  DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect , 1995, Science.

[10]  C. Anderson.  Protein kinases and the response to DNA damage. , 1994, Seminars in cell biology.

[11]  J. Dick,et al.  Rescue of T cell-specific V(D)J recombination in SCID mice by DNA-damaging agents. , 1994, Science.

[12]  T. Jacks,et al.  DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2 , 1994, Cell.

[13]  M. Lenardo,et al.  Sublethal gamma-radiation induces differentiation of CD4-/CD8- into CD4+/CD8+ thymocytes without T cell receptor beta rearrangement in recombinase activation gene 2-/- mice , 1994, The Journal of experimental medicine.

[14]  A. Balmain,et al.  p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis , 1994, Nature Genetics.

[15]  S. Tonegawa,et al.  Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8- thymocyte differentiation. , 1994, Journal of immunology.

[16]  E. White,et al.  Bcl-2 blocks p53-dependent apoptosis , 1994, Molecular and cellular biology.

[17]  A. Strasser,et al.  Bcl-2 expression promotes B- but not T-lymphoid development in scid mice , 1994, Nature.

[18]  R. Weinberg,et al.  Tumor spectrum analysis in p53-mutant mice , 1994, Current Biology.

[19]  T. Jacks,et al.  Sunburn and p53 in the onset of skin cancer , 1994, Nature.

[20]  Yi-Song Wang,et al.  Wild-type p53-triggered apoptosis is inhibited by bcl-2 in a v-myc-induced T-cell lymphoma line. , 1993, Oncogene.

[21]  A. Zlotnik,et al.  Control points in early T-cell development. , 1993, Immunology today.

[22]  A. Zlotnik,et al.  A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. , 1993, Journal of immunology.

[23]  C. Purdie,et al.  Thymocyte apoptosis induced by p53-dependent and independent pathways , 1993, Nature.

[24]  Scott W. Lowe,et al.  p53 is required for radiation-induced apoptosis in mouse thymocytes , 1993, Nature.

[25]  D. Lane.  A death in the life of p53 , 1993, Nature.

[26]  D. Malkin,et al.  p53 and the Li-Fraumeni syndrome. , 1993, Cancer genetics and cytogenetics.

[27]  K. Eichmann,et al.  Regulation of thymocyte development through CD3. I. Timepoint of ligation of CD3 epsilon determines clonal deletion or induction of developmental program , 1993, The Journal of experimental medicine.

[28]  S. Tonegawa,et al.  Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages , 1992, Nature.

[29]  B. Vogelstein,et al.  A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia , 1992, Cell.

[30]  L. Donehower,et al.  Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours , 1992, Nature.

[31]  V. Stewart,et al.  RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement , 1992, Cell.

[32]  B. Vogelstein,et al.  Participation of p53 protein in the cellular response to DNA damage. , 1991, Cancer research.

[33]  Suzanne Cory,et al.  bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship , 1991, Cell.

[34]  A. Rolink,et al.  Molecular and cellular origins of B lymphocyte diversity , 1991, Cell.

[35]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[36]  A. Levine,et al.  The p53 tumour suppressor gene , 1991, Nature.

[37]  A. Giaccia,et al.  scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Carroll,et al.  The SCID mouse mutant: definition, characterization, and potential uses. , 1991, Annual review of immunology.

[39]  R. A. Phillips,et al.  The scid mutation in mice causes a general defect in DNA repair , 1990, Nature.

[40]  Naomi Rosenberg,et al.  The defect in murine severe combined immune deficiency: Joining of signal sequences but not coding segments in V(D)J recombination , 1988, Cell.

[41]  I. Weiler,et al.  Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency , 1986, Cell.

[42]  Y. Becker.  Cancer in ataxia-telangiectasia patients: analysis of factors leading to radiation--induced and spontaneous tumors. , 1986, Anticancer research.

[43]  M. Swift,et al.  Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. , 1986, Journal of the National Cancer Institute.

[44]  M. Potter,et al.  Mechanisms in B-cell neoplasia. , 1986, Immunology today.

[45]  P. Herrlich,et al.  Double-strand break repair and G2 block in Chinese hamster ovary cells and their radiosensitive mutants. , 1985, Mutation research.

[46]  R. Custer,et al.  A severe combined immunodeficiency mutation in the mouse , 1983, Nature.