Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer.
Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer.
复制标题
DOI：
10.1186/bcr3171
复制
发表时间：
2012-04-20
期刊：
影响因子：
--
通讯作者：
Attardi LD
中科院分区：
文献类型：
--
作者：
Dusek RL;Bascom JL;Vogel H;Baron S;Borowsky AD;Bissell MJ;Attardi LD
Perp是p53在DNA损伤诱导的细胞凋亡过程中的转录靶点，也是p63在分层上皮发育过程中的转录靶点。Perp /-小鼠表现出与表皮和口腔粘膜显著起泡相关的出生后死亡率，反映了在角化细胞中桥粒介导的细胞间粘附的关键作用。然而，Perp在其他依赖p63的分层上皮组织中组织稳态中的作用尚不清楚。鉴于p63对乳腺正常发育至关重要，而细胞粘附是确保乳腺上皮正常结构和功能的基础，我们在此研究Perp在乳腺中的功能。免疫荧光和Western blot分析了Perp在小鼠乳腺上皮发育过程中的表达和定位。Perp缺乏对乳腺上皮发育和稳态的影响通过体内乳腺移植试验进行了研究。用Western blot方法比较了多种人乳腺癌细胞系与未转化细胞中的Perp蛋白水平。通过K14-Cre/+衰老队列研究Perp在小鼠乳腺肿瘤发生中的作用；p53fl/fl小鼠为野生型或Perp缺失。分析乳腺肿瘤潜伏期，采用Kaplan-Meier分析评估无瘤生存期。我们发现Perp蛋白在乳腺上皮中表达，在那里它与桥粒共定位。有趣的是，尽管通过Perp基因失活改变桥粒不会显著损害乳腺导管的发育，但Perp基因的缺失会通过引起成熟乳腺上皮周围炎症细胞的积累而影响乳腺上皮的稳态。此外，我们发现与未转化的细胞相比，许多人乳腺癌细胞系中的Perp表达减少。重要的是，Perp缺乏还会促进小鼠乳腺癌的发展。总之，这些观察结果证明了Perp在正常乳腺组织功能和乳腺癌抑制中的重要作用。此外，我们的研究结果强调了桥粒在癌症抑制中的重要性，并建议将Perp作为乳腺癌治疗的潜在预后指标或分子靶点进行评估。
Perp is a transcriptional target of both p53 during DNA damage-induced apoptosis and p63 during stratified epithelial development. Perp-/- mice exhibit postnatal lethality associated with dramatic blistering of the epidermis and oral mucosa, reflecting a critical role in desmosome-mediated intercellular adhesion in keratinocytes. However, the role of Perp in tissue homeostasis in other p63-dependent stratified epithelial tissues is poorly understood. Given that p63 is essential for proper mammary gland development and that cell adhesion is fundamental for ensuring the proper architecture and function of the mammary epithelium, here we investigate Perp function in the mammary gland. Immunofluorescence and Western blot analysis were performed to characterize Perp expression and localization in the mouse mammary epithelium throughout development. The consequences of Perp deficiency for mammary epithelial development and homeostasis were examined by using in vivo mammary transplant assays. Perp protein levels in a variety of human breast cancer cell lines were compared with those in untransformed cells with Western blot analysis. The role of Perp in mouse mammary tumorigenesis was investigated by aging cohorts of K14-Cre/+;p53fl/fl mice that were wild-type or deficient for Perp. Mammary tumor latency was analyzed, and tumor-free survival was assessed using Kaplan-Meier analysis. We show that Perp protein is expressed in the mammary epithelium, where it colocalizes with desmosomes. Interestingly, although altering desmosomes through genetic inactivation of Perp does not dramatically impair mammary gland ductal development, Perp loss affects mammary epithelial homeostasis by causing the accumulation of inflammatory cells around mature mammary epithelium. Moreover, we show reduced Perp expression in many human breast cancer cell lines compared with untransformed cells. Importantly, Perp deficiency also promotes the development of mouse mammary cancer. Together, these observations demonstrate an important role for Perp in normal mammary tissue function and in mammary cancer suppression. In addition, our findings highlight the importance of desmosomes in cancer suppression and suggest the merit of evaluating Perp as a potential prognostic indicator or molecular target in breast cancer therapy.
登录
查看更多内容
影响因子：
2.5
作者：
Hatsell, S;Rowlands, T;Cowin, P
通讯作者：
Cowin, P
影响因子：
15.9
作者：
Conacci-Sorrell, M;Zhurinsky, J;Ben-Ze'ev, A
通讯作者：
Ben-Ze'ev, A
DOI：
10.1083/jcb.132.6.1115
发表时间：
1996-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fialka I;Schwarz H;Reichmann E;Oft M;Busslinger M;Beug H
通讯作者：
Beug H
影响因子：
10.5
作者：
Koster, MI;Kim, S;Roop, DR
通讯作者：
Roop, DR
影响因子：
6.4
作者：
GUELSTEIN, VI;TCHYPYSHEVA, TA;BANNIKOV, GA
通讯作者：
BANNIKOV, GA