Androgen suppressed apoptosis is modified in p53 deficient mice.
Several in vitro studies have provided evidence that the tumor suppressor protein, p53, is involved in the cell death process referred to as apoptosis. The recent development of p53 knock-out mice has enabled further investigation into the function of p53 for apoptosis, in vivo. Radiation-induced apoptosis is suppressed in such mice, yet other forms of apoptosis do not seem to be significantly affected. In this report, we present evidence that such male p53 nullizygous mice have less apoptosis in the prostate glands associated with the first 4 days following castration. Ventral prostate glands were obtained from normal, heterozygous p53-null and p53 nullizygous mice at daily intervals after castration. These tissues were stained for apoptosis with the use of the in situ and labeling method and apoptotic bodies were quantified by microscopy. Although labeled apoptotic bodies were observed in post-castrated tissues from all of these genetic variant mice, the onset of apoptosis was delayed and the occurrence of apoptosis was significantly reduced in the p53 nullizygous mice when compared to normal controls. Heterozygous p53-null mice were intermediate for these criteria. Examination of the internucleosomal DNA fragmentation pattern at 2 days of castration supports a significant diminution of prostate cell apoptosis in nullizygous p53 mice. Additionally, large nucleated and multinucleated cells were detected in the prostate epithelium of noncastrated p53 nullizygous mice and these abnormal cells were increased after castration. Flow cytometric analysis of these tissues confirmed a high number of 4C and 8C DNA content cells in the p53 nullizygous prostates and their frequency was increased by castration. In concordance with an earlier study, we conclude that functional p53 protein is not essential for prostate epithelial cells to undergo castration-induced apoptosis. However, wild-type p53 does appear to enhance this process, especially in the early period following castration, and this protein may regulate an aberrant prostate cell cycling activity that follows castration.
Colombel
M
M
Service d'Urologie C.H.U. Henri Mondor, Créteil, France.
Radvanyi
F
F
Blanche
M
M
Abbou
C
C
Buttyan
R
R
Donehower
L A
LA
Chopin
D
D
Thiery
J P
JP
D000728:Androgens / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D016158:Genes, p53; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009919:Orchiectomy; D011467:Prostate / Q000166:cytology*; D013997:Time Factors
D000728:Androgens