Ectopic expression of Cux1 is associated with reduced p27 expression and increased apoptosis during late stage cyst progression upon inactivation of Pkd1 in collecting ducts

Paul, Binu M.; Vassmer, Dianne; Taylor, Aaron; Magenheimer, Lynn; Carlton, Carol G.; Piontek, Klaus; Germino, Gregory G.; Heuvel, Gregory B. Vanden

doi:10.1002/dvdy.22625

Cited by 13 publications

(19 citation statements)

References 32 publications

(45 reference statements)

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“…Upregulation of CUX1 stimulated proliferation, tumor growth, resistance to apoptosis and angiogenesis in Pnet (8). In the present study, CUX1 functioned as a transactivator for MMP9 transcription and induced the proliferation of pNET cells (potentially through modulating the transcription of certain effectors, for example p21, FGF1, VAV2), which was consistent with previous studies (44)(45)(46).…”

Section: Discussionsupporting

confidence: 93%

THBS2, a microRNA‑744‑5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors

et al. 2020

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The underlying molecular mechanisms of pancreatic neuroendocrine tumor (pNET) development have not yet been clearly identified. The present study revealed that thrombospondin 2 (THBS2) was downregulated in pNET tissues and cells. Forced expression of THBS2 inhibited the proliferation and migration of pNET cells in vitro. MicroRNA(miR)-744-5p was indicated to be a direct regulator of THBS2. Upregulation of miR-744-5p potentially caused THBS2 repression. Furthermore, THBS2 inhibited the production of matrix metalloproteinase (MMP) MMP9 through suppressing the transcriptional activity of CUT-like homeobox 1 (CUX1). CUX1 and MMP9 mediated the effect of THBS2 on pNET proliferation and migration, respectively. The results of the present study revealed a mechanistic role for THBS2 in pNET proliferation and migration, indicating that THBS2 was downregulated by miR-744-5p and further affected the CUX1/MMP9 cascade, which promoted the development of pNET.

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Section: Discussionsupporting

confidence: 93%

THBS2, a microRNA‑744‑5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors

et al. 2020

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“…Kidneys became even more enlarged by P14, with cyst formation throughout the entire kidney (Fig. 3E), comparable to cystic kidneys obtained from Hoxb7-Cre:Pkd1 cond/cond mice (32). These results strongly suggest that the corresponding L4132Δ patient mutation is pathogenic.…”

Section: Resultssupporting

confidence: 75%

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD

Parnell

Magenheimer

Maser

et al. 2018

Human Molecular Genetics

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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of renal cysts that ultimately destroy kidney function. Mutations in the PKD1 and PKD2 genes cause ADPKD. Their protein products, polycystin-1 (PC1) and polycystin-2 (PC2) have been proposed to form a calcium-permeable receptor-channel complex; however the mechanisms by which they function are almost completely unknown. Most mutations in PKD1 are truncating loss-of-function mutations or affect protein biogenesis, trafficking or stability and reveal very little about the intrinsic biochemical properties or cellular functions of PC1. An ADPKD patient mutation (L4132Δ or ΔL), resulting in a single amino acid deletion in a putative G-protein binding region of the PC1 C-terminal cytosolic tail, was found to significantly decrease PC1-stimulated, G-protein-dependent signaling in transient transfection assays. Pkd1ΔL/ΔL mice were embryo-lethal suggesting that ΔL is a functionally null mutation. Kidney-specific Pkd1ΔL/cond mice were born but developed severe, postnatal cystic disease. PC1ΔL protein expression levels and maturation were comparable to those of wild type PC1, and PC1ΔL protein showed cell surface localization. Expression of PC1ΔL and PC2 complexes in transfected CHO cells failed to support PC2 channel activity, suggesting that the role of PC1 is to activate G-protein signaling to regulate the PC1/PC2 calcium channel.

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“…Previous studies show that Cux1 expression is not associated with apoptosis until late in cystic disease 23 and is likely due to tissue damage. Although we have not yet ruled out a role for Cux1 in inflammation, this does not appear to be the case based on kidney histology.…”

Section: Temporal Proliferation Analyses In the Kidneymentioning

confidence: 91%

Proximal Tubule Proliferation Is Insufficient to Induce Rapid Cyst Formation after Cilia Disruption

Sharma

Malarkey

Berbari

et al. 2013

Journal of the American Society of Nephrology

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Disrupting the function of cilia in mouse kidneys results in rapid or slow progression of cystic disease depending on whether the animals are juveniles or adults, respectively. Renal injury can also markedly accelerate the renal cyst formation that occurs after disruption of cilia in adult mice. Rates of cell proliferation are markedly higher in juvenile than adult kidneys and increase after renal injury, suggesting that cell proliferation may enhance the development of cysts. Here, we induced cilia loss in the kidneys of adult mice in the presence or absence of a Cux-1 transgene, which maintains cell proliferation. By using this model, we were able to avoid additional factors such as inflammation and dedifferentiation, which associate with renal injury and may also influence the rate of cystogenesis. After induction of cilia loss, cystic disease was not more pronounced in adult mice with the Cux-1 transgene compared with those without the transgene. In conclusion, these data suggest that proliferation is unlikely to be the sole mechanism underlying the rapid cystogenesis observed after injury in mice that lose cilia function in adulthood.

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Ectopic expression of Cux1 is associated with reduced p27 expression and increased apoptosis during late stage cyst progression upon inactivation of Pkd1 in collecting ducts

Cited by 13 publications

References 32 publications

THBS2, a microRNA‑744‑5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors

THBS2, a microRNA‑744‑5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD

Proximal Tubule Proliferation Is Insufficient to Induce Rapid Cyst Formation after Cilia Disruption

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