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- Title
Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation.
- Authors
Venkatachalam, Sundaresan; Shi, Yu-Ping; Jones, Stephen N.; Vogel, Hannes; Bradley, Allan; Pinkel, Dan; Donehower, Lawrence A.
- Abstract
Tumor suppressor genes are generally viewed as being recessive at the cellular level, so that mutation or loss of both tumor suppressor alleles is a prerequisite for tumor formation. The tumor suppressor gene, p53, is mutated in ∼50% of human sporadic cancers and in an inherited cancer predisposition (LiFraumeni syndrome). We have analyzed the status of the wild-type p53 allele in tumors taken from p53-deficient heterozygous (p53+/) mice. These mice inherit a single null p53 allele and develop tumors much earlier than those mice with two functional copies of wild-type p53. We present evidence that a high proportion of the tumors from the p53+/ mice retain an intact, functional, wild-type p53 allele. Unlike p53+/ tumors which lose their wild-type allele, the tumors which retain an intact p53 allele express p53 protein that induces apoptosis following γ-irradiation, activates p21WAF1/CIP1 and Mdm2 expression, represses PCNA expression (a negatively regulated target of wild-type p53), shows high levels of binding to oligonucleotides containing a wild-type p53 response element and prevents chromosomal instability as measured by comparative genomic hybridization. These results indicate that loss of both p53 alleles is not a prerequisite for tumor formation and that mere reduction in p53 levels may be sufficient to promote tumorigenesis.
- Subjects
TUMOR suppressor genes; GENETIC mutation; CANCER; IRRADIATION; APOPTOSIS; OLIGONUCLEOTIDES; GENOMICS
- Publication
EMBO Journal, 1998, Vol 17, Issue 16, p4657
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/17.16.4657