Gene/Protein
Disease
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Drug
Enzyme
Compound
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Target Concepts:
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Query: UNIPROT:P41181 (
collecting duct
)
5,183
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The antagonism between Mdm2 and its close homolog Mdm4 (also known as MdmX) and
p53
is vital for embryogenesis and organogenesis. Previously, we demonstrated that targeted disruption of Mdm2 in the Hoxb7+ ureteric bud (Ub) lineage, which gives rise to the renal collecting system, causes renal hypodysplasia culminating in perinatal lethality. In this study, we examine the unique role of Mdm4 in establishing the
collecting duct
system of the murine kidney. Hoxb7Cre driven loss of Mdm4 in the Ub lineage (Ub
Mdm4-/-
) disrupts branching morphogenesis and triggers UB cell apoptosis. Ub
Mdm4-/-
kidneys exhibit abnormally dilated Ub tips while the medulla is hypoplastic. These structural alterations result in secondary depletion of nephron progenitors and nascent nephrons. As a result, newborn Ub
Mdm4-/-
mice have hypo-dysplastic kidneys. Transcriptional profiling revealed downregulation of the Ret-tyrosine kinase pathway components, Gdnf, Wnt11, Sox8, Etv4 and Cxcr4 in the Ub
Mdm4-/-
mice relative to controls. Moreover, the expression levels of the canonical Wnt signaling members Axin2 and Wnt9b are downregulated. Mdm4 deletion upregulated
p53
activity and
p53
-target gene expression including Cdkn1a (p21), Gdf15, Ccng1, PERP, and Fas. Germline loss of
p53
in Ub
Mdm4-/-
mice largely rescues kidney development and terminal differentiation of the
collecting duct
. We conclude that Mdm4 plays a unique and vital role in Ub branching morphogenesis and collecting system development.
...
PMID:Mdm4 controls ureteric bud branching via regulation of p53 activity. 3246 96
Background:
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of the
PKD1
and
PKD2
genes. Dysregulation of the expression of PKD genes, the abnormal activation of PKD associated signaling pathways, and the expression and maturation of miRNAs regulates cyst progression. However, the upstream factors regulating these abnormal processes in ADPKD remain elusive.
Methods:
To investigate the roles of an RNA helicase, p68, in ADPKD, we performed Western blot and qRT-PCR analysis, immunostaining and ChIP assay in cystic renal epithelium cells and tissues.
Results:
We found that p68 was upregulated in cystic renal epithelial cells and tissues. p68 represses
Pkd1
gene expression via transcriptional and posttranscriptional mechanisms in renal epithelial cells, in that 1) p68 binds to the promoter of the
Pkd1
gene together with
p53
to repress transcription; and 2) p68 promotes the expression and maturation of miR-17, miR-200c and miR-182 and via these miRNAs, post-transcriptionally regulates the expression of
Pkd1
mRNA. Drosha is involved in this process by forming a complex with p68. p68 also regulates the phosphorylation and activation of PKD proliferation associated signaling and the expression of fibrotic markers in
Pkd1
mutant renal epithelial cells. Silence of p68 delays cyst formation in
collecting duct
cell mediated 3D cultures. In addition, the expression of p68 is induced by H
2
O
2
-dependent oxidative stress and DNA damage which causes downregulation of
Pkd1
transcription in cystic renal epithelial cells and tissues.
Conclusions:
p68 plays a critical role in negatively regulating the expression of the
PKD1
gene along with positively regulating the expression and maturation of miRNAs and activation of PKD associated signaling pathways to cause renal cyst progression and fibrosis in ADPKD.
...
PMID:RNA helicase p68 inhibits the transcription and post-transcription of
Pkd1
in ADPKD. 3272 71
End-stage renal disease (ESRD) patients on dialysis therapy have a higher incidence of renal cell carcinomas (RCCs), which consist of 2 major histopathological types: clear-cell RCCs (ESRD-ccRCCs) and acquired cystic disease (ACD)-associated RCCs. However, their genetic and epigenetic alterations are still poorly understood. Here, we investigated somatic mutations, copy number alterations (CNAs), and DNA methylation profiles in 9 ESRD-ccRCCs and 7 ACD-associated RCCs to identify their molecular alterations and cellular origins. Targeted sequencing of 409 cancer-related genes, including VHL, PBRM1, SETD2, BAP1, KDM5C, MET, KMT2C (MLL3), and
TP53
, showed ESRD-ccRCCs harbored frequent VHL mutations, while ACD-associated RCCs did not. CNA analysis showed that ESRD-ccRCCs had a frequent loss of chromosome 3p while ACD-associated RCCs had a gain of chromosome 16. Beadarray methylation analysis showed that ESRD-ccRCCs had methylation profiles similar to those of sporadic ccRCCs, while ACD-associated RCCs had profiles similar to those of papillary RCCs. Expression analysis of genes whose expression levels are characteristic to individual segments of a nephron showed that ESRD-ccRCCs and ACD-associated RCCs had high expression of proximal tubule cell marker genes, while chromophobe RCCs had high expression of distal tubule cell/
collecting duct
cell marker genes. In conclusion, ESRD-ccRCCs and ACD-associated RCCs had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively, and these 2 histopathological types of RCCs were indicated to have originated from proximal tubule cells of the nephron.
...
PMID:Genetic and epigenetic profiling indicates the proximal tubule origin of renal cancers in end-stage renal disease. 3286 Mar 4
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