Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 2, Pages 704-709Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1015027108
Keywords
retinoblastoma gene; cellular senescence; mouse model
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Funding
- National Institutes of Health [CA70292, CA126505, CA96823]
- Department of Defense [W81XWH-07-1-0154]
- National Cancer Institute's Cancer Center [CA016056, CA68485]
- Vanderbilt University Medical Center [CA68485]
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Mutational inactivation of the RB1 tumor suppressor gene initiates retinoblastoma and other human cancers. RB1 protein (pRb) restrains cell proliferation by binding E2f transcription factors and repressing the expression of cell cycle target genes. It is presumed that loss of pRb/E2f interaction accounts for tumor initiation, but this has not been directly tested. RB1 mutation is a late event in other human cancers, suggesting a role in tumor progression as well as initiation. It is currently unknown whether RB1 mutation drives tumor progression and, if so, whether loss of pRb/E2f interaction is responsible. We have characterized tumorigenesis in mice expressing a mutant pRb that is specifically deficient in binding E2f. In endocrine tissue, the mutant pRb has no detectable effect on tumorigenesis. In contrast, it significantly delays progression to invasive and lethal prostate cancer. Tumor delay is associated with induction of a senescence response. We conclude that the pRb/E2f interaction is critical for preventing tumor initiation, but that pRb can use additional context-dependent mechanisms to restrain tumor progression.
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