p53 deficiency provokes urothelial proliferation and synergizes with activated Ha-ras in promoting urothelial tumorigenesis.
Mutation and deletion of the p53 tumor suppressor gene are arguably the most prevalent among the multiple genetic alterations found in human bladder cancer, but these p53 defects are primarily associated with the advanced diseases, and their roles in bladder tumor initiation and in synergizing with oncogenes in tumor progression have yet to be defined. Using the mouse uroplakin II gene promoter, we have targeted into urothelium of transgenic mice a dominant-negative mutant of p53 that lacks the DNA-binding domain but retains the tetramerization domain. Urothelium-expressed p53 mutant binds to and stabilizes the endogenous wild-type p53, induces nuclear abnormality, hyperplasia and occasionally dysplasia, without eliciting frank carcinomas. Concurrent expression of the p53 mutant with an activated Ha-ras, the latter of which alone induces urothelial hyperplasia, fails to accelerate tumor formation. In contrast, the expression of the activated Ha-ras in the absence of p53, as accomplished by crossing the activated Ha-ras transgenic mice with the p53 knockout mice, results in early-onset bladder tumors that are either low-grade superficial papillary or high grade in nature. These results provide the first in vivo experimental evidence that p53 deficiency predisposes the urothelium to hyperproliferation, but is insufficient for bladder tumorigenesis; that the mere reduction of p53 dosage, as produced in transgenic mice expressing the dominant-negative p53 or in heterozygous p53 knockouts, is incapable of synergizing with Ha-ras to induce bladder tumors; and that the complete loss of p53 is a prerequisite for collaborating with activated Ha-ras to promote bladder tumorigenesis.
Gao
Jing
J
Veterans Affairs Medical Center in New York, NY 10010, USA.
Huang
Hong-Ying
HY
Pak
Joanne
J
Cheng
Jin
J
Zhang
Zhong-Ting
ZT
Shapiro
Ellen
E
Pellicer
Angel
A
Sun
Tung-Tien
TT
Wu
Xue-Ru
XR
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics*; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000166:cytology* / Q000473:pathology
D017931:DNA Primers