|
 |
|
|
| The EMBO Journal
(1998) 17, 4657–4667, doi:10.1093/emboj/17.16.4657 |
|
| Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation |
|
|
| Sundaresan Venkatachalam1, Yu-Ping Shi2, Stephen N. Jones1, 3, Hannes Vogel4, Allan Bradley3, Dan Pinkel2 and Lawrence A. Donehower1 |
|
|
1 Division of Molecular Virology and Department of Cell Biology, Houston, TX 77030, USA 2 Division of Molecular Cytometry, Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA 3 Department of Molecular and Human Genetics and Howard Hughes Medical Institute, Houston, TX 77030, USA 4 Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA Received 21 November 1997; Revised 3 June 1998; Accepted 25 June 1998. |
|
|
|
| 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 (Li–Fraumeni 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  -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. |
|
| Keywords: genomic instability, loss of heterozygosity, mouse, p53, tumor suppressor |
|
|
| |
| |
| |
 | Email link to a friend |
| |
 | Download PDF |
| |
 | Full text |
| |
| |
| |
 | Next article |
| |
 | Previous article |
| |
 | Table of contents |
| |
| |
 | Rights and permissions |
| |
 | Reprints |
| |
| |
| |
 Register for table of contents by email | |
| |
| |
| |
