Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53.
We have used an in vivo tumor model to evaluate the consequences of p53 tumor suppressor protein deficiency in a tissue-specific context. By breeding MMTV-ras transgenic mice, which are highly susceptible to the development of mammary and salivary tumors, with p53(-/-) mice, we generated three classes of animals which contained the MMTV-ras transgene but differed in their p53 functional status (ras/p53(+/+), ras/p53(+/-), or ras/p53(-/-)). ras/p53(-/-) mice developed tumors more rapidly than animals of the other two genotypes; however, the distribution of tumors was unexpectedly altered. Whereas the most frequently observed tumors in ras/p53(+/+) and ras/p53(+/-) mice were of mammary origin, ras/p53(-/-) mice developed primarily salivary tumors. In addition, the mammary and salivary tumors from ras/p53(-/-) mice consistently exhibited a number of unfavorable characteristics, including higher histologic grades, increased growth rates, and extensive genomic instability and heterogeneity, relative to tumors from ras/p53(+/+) mice. Interestingly, the increased growth rates of ras/p53(-/-) tumors appear to be due to impaired cell cycle regulation rather than decreased apoptosis, suggesting that p53-mediated tumor suppression can occur independent of its role in apoptosis.
Hundley
J E
JE
Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 78284, USA.
Koester
S K
SK
Troyer
D A
DA
Hilsenbeck
S G
SG
Subler
M A
MA
Windle
J J
JJ
D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D003433:Crosses, Genetic; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D018740:Genetic Heterogeneity; D005838:Genotype; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D014412:Tumor Virus Infections / Q000235:genetics* / Q000473:pathology
D016159:Tumor Suppressor Protein p53