Jerry D J, Kuperwasser C, Downing S R, Pinkas J, He C, Dickinson E, Marconi S, Naber S P
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst 01003, USA.
Oncogene. 1998 Nov 5;17(18):2305-12. doi: 10.1038/sj.onc.1202157.
In mammals, weaning of neonates and subsequent milk stasis initiates removal of the secretory epithelium of the mammary gland by apoptosis. The p53 tumor suppressor gene is induced rapidly following weaning of neonates, but its role in the process of involution has not been defined. Therefore, experiments were performed to identify the cell types in which the p53 gene is expressed during involution and determine the consequences of its absence in BALB/c-p53null mice. Both p53 mRNA and protein were detected in the mammary epithelium within 48 h following weaning and resulted in an eightfold increase in levels of p21WAF1 mRNA. Induction of p21WAF1 mRNA was absent in BALB/c-p53null mice, and therefore, was shown to be p53-dependent. The BALB/c-p53null mice exhibited delayed involution of the mammary epithelium, as measured by 60% greater epithelial area compared to BALB/c-p53(wt) mice through 5 days post-weaning. The delay was transient with no differences being apparent at 7 days post-weaning. Expression of the stromal protease stromelysin-1 was unaffected by the absence of p53 suggesting that stromal responses were intact. These data demonstrate that p53 participates in the first stage of involution initiated by the epithelium itself, but does not affect the second phase during which stromal proteases are induced.
在哺乳动物中，新生幼崽断奶及随后的乳汁淤积会引发乳腺分泌上皮细胞通过凋亡被清除。新生幼崽断奶后，p53肿瘤抑制基因会迅速被诱导表达，但其在乳腺退化过程中的作用尚未明确。因此，开展了实验以确定在退化过程中表达p53基因的细胞类型，并确定BALB/c-p53基因敲除小鼠中缺乏该基因的后果。断奶后48小时内，在乳腺上皮细胞中检测到了p53 mRNA和蛋白，且p21WAF1 mRNA水平增加了八倍。在BALB/c-p53基因敲除小鼠中未检测到p21WAF1 mRNA的诱导表达，因此表明其诱导表达依赖于p53。通过测量断奶后5天内的上皮面积，发现BALB/c-p53基因敲除小鼠的乳腺上皮细胞退化延迟，与BALB/c-p53（野生型）小鼠相比，上皮面积大60%。这种延迟是短暂的，断奶后7天时无明显差异。基质蛋白酶基质溶解素-1的表达不受p53缺失的影响，这表明基质反应是完整的。这些数据表明，p53参与了由上皮细胞自身启动的退化第一阶段，但不影响诱导基质蛋白酶的第二阶段。
