Lanoix J, D'Agati V, Szabolcs M, Trudel M
Institut de Recherches Cliniques de Montréal, Faculté de Médicine del'Université de Montréal, Québec, Canada.
Oncogene. 1996 Sep 19;13(6):1153-60.
The proto-oncogene c-myc has been implicated in both cellular proliferation and apoptosis, and we have shown that overexpression of c-myc can induce polycystic kidney disease in transgenic mice. To elucidate the molecular and cellular defects underlying cystogenesis, we have investigated the potential roles of cell proliferation and apoptosis as they relate to c-myc and modulators of c-myc function in human autosomal dominant polycystic kidney disease (ADPKD). Renal c-myc expression was consistently elevated, up to 15-fold, in ADPKD. High levels of c-myc expression correlated with 10- to 100-fold increased proliferation index in cystic epithelium. Interestingly, steady-state levels of bcl-2 mRNA were also increased up to 20-fold and Bcl-2 protein was markedly elevated. In contrast, the expression of bax and p53 was virtually unchanged. However, apoptosis was consistently and significantly increased in ADPKD kidneys, unchecked by high levels of Bcl-2. Together with proliferation, apoptosis may thus represent a general mechanism for cyst growth and tissue remodeling. We conclude that both epithelial cell proliferation and apoptosis required for normal kidney homeostasis are deregulated in ADPKD, recapitulating the renal developmental program. Furthermore, abnormal expression of proto-oncogenes regulating these processes is an important mediator of cystogenesis in human ADPKD.
原癌基因c-myc与细胞增殖和凋亡均有关联，并且我们已经表明c-myc的过表达可在转基因小鼠中诱发多囊肾病。为了阐明囊肿形成背后的分子和细胞缺陷，我们研究了细胞增殖和凋亡在人类常染色体显性多囊肾病（ADPKD）中与c-myc及其功能调节剂相关的潜在作用。在ADPKD中，肾脏c-myc表达持续升高，最高可达15倍。c-myc的高表达水平与囊性上皮细胞中增殖指数增加10至100倍相关。有趣的是，bcl-2 mRNA的稳态水平也增加了高达20倍，并且Bcl-2蛋白明显升高。相比之下，bax和p53的表达几乎没有变化。然而，ADPKD肾脏中的凋亡持续且显著增加，并未受到高水平Bcl-2的抑制。因此，与增殖一起，凋亡可能代表囊肿生长和组织重塑的一般机制。我们得出结论，在ADPKD中，正常肾脏稳态所需的上皮细胞增殖和凋亡均失调，重现了肾脏发育程序。此外，调节这些过程的原癌基因的异常表达是人类ADPKD囊肿形成的重要介导因素。
