Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
Analysis of mice with mutations in the tumor-suppressor genes RB, NF-1 and p53 (Meeting abstract).
Proc Annu Meet Am Assoc Cancer Res; 34:610-1 1993. Unique Identifier : AIDSLINE ICDB/93694365 Jacks T; Dept. of Biology, Center for Cancer Res., Massachusetts Inst. of; Technology, Cambridge, MA 02139
Abstract:
The homozygous inactivation of tumor-suppressor genes is a common event in the genesis of a large number of human cancers. In addition, individuals who inherit a defective allele of one of several tumor suppressor genes are strongly predisposed to malignancy. In an effort to understand the tumorigenic effects of tumor-suppressor gene mutations and to study the role of these genes in normal cells and in development, we have created mouse strains carrying germline mutations in several of them. Gene targeting in ES cells was used to construct animals that are heterozygous for mutations in Rb, NF-1 or p53. For each of these genes, targeting was accomplished using the positive-negative selection method; targeting efficiencies ranged from approx 2% to 20% of doubly selected cells. Studies in these mice indicate that although the target cell for tumorigenesis differs between mice and humans, the mechanism of transformation is similar. The developmental requirements for these tumor-suppressor gene mutations have been determined by crossing the mutations to homozygosity. We have observed embryonic lethality for both Rb and NF-1 homozygotes at approx day 14 and 13 of gestation, respectively. We find that p53 function is not required for normal development in the mouse. However, p53-deficient mice are highly predisposed to malignancy, with the majority of animals developing lymphoma in the first 3-4 mo of life. The lymphomas typically affect the thymus, and these are composed of CD4+/CD8+ T cells. We have also used these animals as sources of mutant cells with which to study the function of tumor-suppressor genes in vitro and found that in some contexts, p53 function is required for programmed cell death, but it is not an obligatory component of all apoptotic pathways. This observation may also explain the predisposition of p53+/- animals toward lymphomagenesis, since the thymocytes sensitive to apoptosis are CD4+/CD8+. These data indicate at least three mechanisms by which loss of p53 function can contribute to tumorigenesis: gene amplification, increased mutation following DNA damage, and inappropriate cell survival. Given the recent evidence suggesting that p53 acts as a transcriptional regulator, we are interested in the target genes that mediate these various cellular processes. Although our analysis to date has focused on the effects of individual tumor-suppressor gene mutations in the context of the whole animal or in cells in vitro, we are also interested in the effects of combining these mutations. Compound mutants will be valuable in assessing synergism between tumor-suppressor gene mutation in vivo and will also yield cells that are defective in multiple cell cycle control pathways. (5 Refs)
Keywords: Animal Cell Death CD4-CD8 Ratio Genes, Neurofibromatosis 1/*GENETICS Genes, Retinoblastoma/*GENETICS G1 Phase Homozygote Human Li-Fraumeni Syndrome/GENETICS Lymphoma/GENETICS/PATHOLOGY Mice *Mutation Osteosarcoma/GENETICS Protein p53/*GENETICS ABSTRACT 931230
M93C0826
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Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
