Article

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation.

Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Journal of Clinical Investigation (Impact Factor: 13.77). 05/2005; 115(4):910-8. DOI: 10.1172/JCI22850
Source: PubMed

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is the most common human monogenic genetic disorder and is characterized by progressive bilateral renal cysts and the development of renal insufficiency. The cystogenesis of ADPKD is believed to be a monoclonal proliferation of PKD-deficient (PKD(-/-)) renal tubular epithelial cells. To define the function of Pkd1, we generated chimeric mice by aggregation of Pkd1(-/-) ES cells and Pkd1(+/+) morulae from ROSA26 mice. As occurs in humans with ADPKD, these mice developed cysts in the kidney, liver, and pancreas. Surprisingly, the cyst epithelia of the kidney were composed of both Pkd1(-/-) and Pkd1(+/+) renal tubular epithelial cells in the early stages of cystogenesis. Pkd1(-/-) cyst epithelial cells changed in shape from cuboidal to flat and replaced Pkd1(+/+) cyst epithelial cells lost by JNK-mediated apoptosis in intermediate stages. In late-stage cysts, Pkd1(-/-) cells continued immortalized proliferation with downregulation of p53. These results provide a novel understanding of the cystogenesis of ADPKD patients. Furthermore, immortalized proliferation without induction of p53 was frequently observed in 3T3-type culture of mouse embryonic fibroblasts from Pkd1(-/-) mice. Thus, Pkd1 plays a role in preventing immortalized proliferation of renal tubular epithelial cells through the induction of p53 and activation of JNK.

0 Bookmarks
 · 
75 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal monogenic disorder, with more than 12 million cases worldwide. The two causative genes for ADPKD, PKD1 and PKD2, encode protein products polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. Recent data have shed light on the role of PC1 in regulating the severity of the cystic phenotypes in ADPKD, autosomal recessive polycystic kidney disease (ARPKD), and isolated autosomal dominant polycystic liver disease (ADPLD). These studies showed that the rate for cyst growth was a regulated trait, a process that can be either sped up or slowed down by alterations in functional PC1. These findings redefine the previous understanding that cyst formation occurs as an “on-off” process. Here we review these and other related studies with an emphasis on their translational implications for polycystic diseases.
    Trends in Molecular Medicine 02/2014; DOI:10.1016/j.molmed.2014.01.004 · 10.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Protein kinase D1 (PKD1 or PKCμ) is a serine/threonine kinase which contributes to malignant progression, including cell growth, apoptosis, motility, and angiogenesis. Although B- and T-cells express multiple PKC family members, modulation of individual PKC isoforms in association with Epstein-Barr virus (EBV) infection has not been evaluated. In this study we examined the effects of PKD1 as a cellular target of EBV latent membrane protein-1 (LMP1) on the response of malignant B cell lines to rituximab and doxorubicin. LMP1 up-regulated PKD1 in malignant B-cells (BJAB, DG75, Namalwa and Toledo) but not in T-cells (Jurkat, HuT78, and H9). Interestingly, LMP1 stabilized PKD1 protein through direct interaction, which contributed to the survival of rituximab- or doxorubicin-treated malignant B cells. In the absence of PKD1, LMP1 was unable to up-regulate Mcl-1 in doxorubicin-treated malignant B-cells. Also, PH domain phosphorylation and activation loop phosphorylation of PKD1 was critical for LMP1-mediated cell survival. PKD1 knockdown was found to be an efficient strategy to overcome rituximab- or doxorubicin-resistance caused by LMP1 expression. Therefore, PKD1 could be a molecular target for therapeutic intervention in the EBV-associated B-cell lymphoma treatment with rituximab or doxorubicin.
    Leukemia & lymphoma 04/2014; 56(1). DOI:10.3109/10428194.2014.911860 · 2.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited genetic diseases, caused by mutations in PKD1 and/ or PKD2. Infertility and reproductive tract abnormalities in male ADPKD patients are very common and have higher incidence than in the general population. In this work, we reveal novel roles of Pkd2 for male reproductive system development. Disruption of Pkd2 caused dilation of mesonephric tubules/efferent ducts, failure of epididymal coiling, and defective testicular development. Deletion of Pkd2 in the epithelia alone was sufficient to cause reproductive tract defects seen in Pkd2−/− mice, suggesting that epithelial Pkd2 plays a pivotal role for development and maintenance of the male reproductive tract. In the testis, Pkd2 also plays a role in interstitial tissue and testicular cord development. In-depth analysis of epithelial-specific knockout mice revealed that Pkd2 is critical to maintain cellular phenotype and developmental signaling in the male reproductive system. Taken together, our data for the first time reveal novel roles for Pkd2 in male reproductive system development and provide new insights in male reproductive system abnormality and infertility in ADPKD patients.
    Differentiation 03/2014; DOI:10.1016/j.diff.2014.04.001 · 2.84 Impact Factor

Full-text (2 Sources)

Download
0 Downloads
Available from
Mar 27, 2015