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Astrocytes derived from p53-deficient mice provide a multistep in vitro model for development of malignant gliomas.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 1995 Aug; Vol. 15 (8), pp. 4249-59. - Publication Year :
- 1995
-
Abstract
- Loss or mutation of p53 is thought to be an early event in the malignant transformation of many human astrocytic tumors. To better understand the role of p53 in their growth and transformation, we developed a model employing cultured neonatal astrocytes derived from mice deficient in one (p53 +/-) or both (p53 -/-) p53 alleles, comparing them with wild-type (p53 +/+) cells. Studies of in vitro and in vivo growth and transformation were performed, and flow cytometry and karyotyping were used to correlate changes in growth with genomic instability. Early-passage (EP) p53 -/- astrocytes achieved higher saturation densities and had more rapid growth than EP p53 +/- and +/+ cells. The EP p53 -/- cells were not transformed, as they were unable to grow in serum-free medium or in nude mice. With continued passaging, p53 -/- cells exhibited a multistep progression to a transformed phenotype. Late-passage p53 -/- cells achieved saturation densities 50 times higher than those of p53 +/+ cells and formed large, well-vascularized tumors in nude mice. p53 +/- astrocytes exhibited early loss of the remaining wild-type p53 allele and then evolved in a manner phenotypically similar to p53 -/- astrocytes. In marked contrast, astrocytes retaining both wild-type p53 alleles never exhibited a transformed phenotype and usually senesced after 7 to 10 passages. Dramatic alterations in ploidy and karyotype occurred and were restricted to cells deficient in wild-type p53 following repeated passaging. The results of these studies suggest that loss of wild-type p53 function promotes genomic instability, accelerated growth, and malignant transformation in astrocytes.
- Subjects :
- Animals
Blotting, Southern
Cell Division drug effects
Crosses, Genetic
DNA, Neoplasm genetics
Fibroblast Growth Factor 2 genetics
Fibroblast Growth Factor 2 pharmacology
Flow Cytometry
Glioma blood supply
Glioma genetics
Glioma pathology
Immunohistochemistry
Karyotyping
Mice
Mice, Inbred Strains
Mice, Transgenic
Neoplasms, Experimental
Oligonucleotides, Antisense
Astrocytes pathology
Cell Transformation, Neoplastic
Disease Models, Animal
Glioma etiology
Tumor Suppressor Protein p53 deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 15
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 7623819
- Full Text :
- https://doi.org/10.1128/MCB.15.8.4249