Last update: June 1998
The combinatorial effects of p53-deficiency and other genes mediating tumor predisposition has led to illuminating and, in some cases, surprising insights into the role of cooperating oncogenes and tumor suppressor genes in the tumorigenesis process. With the recent development of the DNA repair gene knockout mice, perhaps further such interesting synergies will be detected when these mice are crossed to the p53-deficient mice.
Transgenic mouse models expressing an activated oncogene or an inactivated tumor suppressor or DNA repair gene have been shown to be experimentally manipulable models for studying the multistep nature of tumorigenesis (1). The transgenic models, particularly some of the tumor suppressor and DNA repair knockout mice, are comparable to humans with cancer predisposition syndromes (2-3). They are both primed for early tumor development because of a predisposing germ line mutation. Yet both require additional cooperating mutations as a prerequisite for emergence of a tumor cell. The nature of these cooperating lesions is only beginning to be elucidated in human and animal model systems.
With transgenic animal models, the cooperativity of candidate genes in oncogenesis can be functionally assessed in an organismal context by crossing of two animals, each bearing an oncogenic transgene or knockout allele. If the bitransgenic offspring of the cross develop tumors at a rate significantly faster than both of the parents, then cooperativity has occurred. Cooperativity implies that the two cooperating genes contribute to tumorigenesis through non-identical growth signal transduction pathways. If both genes are on identical signal transduction pathways (e.g. ras and raf), it seems unlikely that the combination of two such genes would accelerate tumorigenesis.
We and others have begun to assess the cooperativity of the p53 tumor suppressor gene with other genes through crossing of the p53 knockout mouse with other transgenic mice predisposed to cancer. Since p53 mutations are associated with almost half of all human cancers (4), the identification of cooperating genes may provide important new mechanistic insights into p53-associated tumorigenesis pathways. The p53-/- and p53+/- knockout mice are already quite tumor prone, with a mean time to tumor of about 4.5 months and 18 months, respectively (5-8). However, in a number of crosses, it is possible to significantly accelerate these incidences, as shown in Table 1 below. For example, combined Rb and p53 deficient mice show accelerated tumor incidences in comparison to their monodeficient parents (9,10). This is consistent with the observation of combined p53 and Rb mutations in some human tumor types (9). In contrast, no acceleration of tumorigenesis was observed in p53-/- bcl-2 transgenic mice (11), suggesting the possibility that these two genes may contribute to the same tumorigenesis pathway.
In some cases, the bitransgenic animals exhibit tumor types not observed in either parent (Table 1). Interestingly, such novel tumor types in bitransgenic offspring were only observed when two tumor suppressor gene knockout mice were crossed, suggesting cooperativity to alter target tissue specificity for tumorigenesis. In other cases (e.g. the myc/p53 crosses), the bitransgenic offspring developed tumors of the parental type, but these tended to be more aggressive and more metastatic (12,13).
Table 1:
Cooperativity between p53 and Other Genes in Mouse Models| Cooperating Gene | Nature of Gene | Site of Expression | Tumor Type(s) | Synergy with p53-/-? | Synergy with p53+/-? | Novel tumors | References |
| Rb | knockout | global | pituitary, adenomas | yes | yes | yes, islet cells, pinealoblastomas | 9, 10 |
| mutant p53 | transgene | global | lymphomas, lungtumors, osteosarcomas | no | yes | no | 14 |
| myc (1) | transgene | mammary gland | mammary tumors | ND | no | no | 12 |
| myc (2) | transgene | T-cells | lymphomas | yes | yes | no | 13 |
| bcl-2 | transgene | B-cells | lymphomas | no | ND | no | 11 |
| mdm-2 | knockout | global | none | no | in progress | no | 15 |
| SCID | natural mutation | lymphoid cells | lymphomas | yes | ? | no | 16 |
| APC | chemically induced mutation | global | intestinal tumors | no | no | yes, desmoid and pancreatic tumors | 17,18 |
| Wnt-1 | transgene | mammary gland | mammary tumors | yes | no | no | 19 info on mice |
| NF-1 | knockout | global | pheochromocytomas, myeloid leukemia | ? | yes | yes, rhabdomyosarcomas | 16 |
table
References
(1) Christofori, G. and Hanahan, D. (1994). Molecular dissection of multi-stage tumorigenesis in transgenic mice. Sem. Cancer Biol. 5:3-12.
(2) Kumar, T.R., Donehower, L.A., Bradley, A., and Matzuk, M.M. (1995). Transgenic mouse models for tumour-suppressor genes. J. Int. Med. 233-238.
(3) Jones, S.N., Donehower, L.A., and Bradley, A. (1995). Analysis of tumor suppressor genes using transgenic mice. Methods: A Companion to Methods in Enzymology 8:247-258.
(4) Greenblatt, M.S., Bennett, W.P., Hollstein, M., and Harris, C.C. (1994). Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54:4855-4878.
(5) Donehower, L.A., Harvey, M., Slagle, B.L., McArthur, M.J., Montgomery, C.A., Jr., Butel, J.S., and Bradley, A. (1995). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215-221.
(6) Harvey, M., McArthur, M.J., Montgomery, C.A., Jr., Butel, J.S., Bradley, A., and Donehower, L.A. (1993). Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nature Genet. 5:225-229.
(7) Jacks T., Remington L., Williams B.O., Schmitt, E., Halachi, S., Bronson, R., and Weinberg, R.A. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4:1-7, 1994.
(8) Purdie C.A., Harrison D.J., Peter A., Dobbie, L., White, S., Howie, S.E.M., Salter, D.M., Bird, C.C., Wyllie, A.H., Hooper, M.L., and Clarke, A. Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene 9:603-609, 1994.
(9) Williams, B.O., Remington, L., Albert, D.M., Mukai, S., Bronson, R.T., and Jacks, T. (1994). Cooperative tumorigenic effects of germline mutations in Rb and p53. Nature Genet. 7:480-484.
(10) Harvey, M., Vogel, H., Lee, E.Y.H.-P., Bradley, A., and Donehower, L.A. (1995). Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res. 55:1146-1151.
(11) Marin, M.C., Hsu, B., Meyn, R., Donehower, L.A., El-Naggar, A.K., and McDonnell, T.J. (1994). Evidence that p53 and bcl-2 are regulators of a common cell death pathway important for in vivo lymphomagenesis. Oncogene 9:3107-3112.
(12) Elson, A., Deng, C., Campos-Torres, J., Donehower, L.A., and Leder, P. (1995). The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice. Oncogene 11:181-190.
(13) Blyth, K., Terry, A., O'Hara, M., Baxter, E.W., Campbell, M., Stewart, M., Donehower, L.A., Onions, D.E., Neil, J.C., and Cameron, E.R. (1995). Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: early and late effects of p53 loss. Oncogene 10:1717-1723.
(14) Harvey, M., Vogel, H., Danna Morris, Bradley, A., Bernstein, A., and Donehower, L.A. (1995). A mutant p53 transgene accelerates tumour development in heterozygous but not nullizygous p53-deficient mice. Nature Genet. 9:305-311.
(15) Steve Jones, unpublished data
(16) Tyler Jacks, personal communication
(17) Bill Dove, personal communication
(18) Clarke, A.R., Cumings, M.C., and Harrison, D.J. (1995). Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy. Oncogene 11:1913-1920.
(19) Donehower, L.A., Godley, L.A., Aldaz, C.M., Pyle, R., Shi, Y., Pinkel, D., Gray, J., Medina, D., Bradley, A., and Varmus, H.E. (1995). Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes & Develop. 9:882-895. (info about mice)
contributed by Larry Donehower
Larry Donehower
Baylor College of Medicine
Phone: 713-798-3594
Fax: 713-798-3490
e-mail: larryd@bcm.tmc.edu
Last update: June 1998 |