Acceleration of polycystic kidney disease progression in cpk mice carrying a deletion in the homeodomain protein Cux1

Alcalay, Neal I.; Sharma, Madhulika; Vassmer, Dianne; Chapman, Brandon C.; Paul, Binu M.; Zhou, Jing; Brantley, Jennifer G.; Wallace, Darren P.; Maser, Robin L.; Heuvel, Gregory B. Vanden

doi:10.1152/ajprenal.90420.2008

Cited by 29 publications

(47 citation statements)

References 72 publications

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“…Cux1 is a homeobox gene that represses the cyclin kinase inhibitors p21 and p27, and transgenic mice ectopically expressing Cux1 develop renal hyperplasia (107). A 246-amino acid deletion in Cux1 accelerates PKD progression in the cpk model of ARPKD (11), and the ensuing phenotype was explained by a missing cathepsin L cleavage site in the truncated Cux1 mutant, which thereby maintains increased tubular cell proliferation and apoptosis. Cux1 is proteolytically processed by a nuclear isoform of cathepsin L (10).…”

Section: Figurementioning

confidence: 99%

“…In both human ADPKD cells and in kidneys of mice with a targeted deletion in Pkd1, a murine model of PKD, decreased nuclear cathepsin L levels are associated with increased levels of Cux1 protein in the cystic cells in vitro and the cysts in vivo (11). These results suggest a mechanism by which reduced Cux1 processing by nuclear cathepsin L results in the accumulation of Cux1, downregulation of p21/p27, and increased cell proliferation in PKD (11). Furthermore, they provide proof of principle of the hypothesis that nuclear cathepsin L is capable of processing transcription factors that control important cellular programs, such as growth.…”

Section: Figurementioning

confidence: 99%

“…In general, the cysteine cathepsins are stable in acidic cellular compartments, i.e., in lysosomes and endosomes, and capable of efficiently cleaving a wide variety of substrates. Despite this, during the past decade, important and specific functions of cathepsins have been discovered to occur extracellularly and in other locations inside cells, such as secretory vesicles (5,6), the cytosol (7)(8)(9), and the nucleus (10,11). When studying the function of cathepsins, one needs to consider species differences between humans and mice (Table 1 and Sidebar 2).…”

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confidence: 99%

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Specialized roles for cysteine cathepsins in health and disease

Reiser

Adair²,

Reinheckel³

2010

J. Clin. Invest.

502

403

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A primer on cathepsin biology Cathepsin L transcription and translation. Substantial work has beendone to analyze the promoter regions of the human cathepsin L gene (CTSL) promoter as well as to understand the regulation of different splice variants within the 5′ untranslated region of the transcript (21,22). Of note, one of the splice variants contains a functional internal ribosomal entry site that enables ongoing translation of human cathepsin L under stress conditions, and hypoxia can shut down cap-dependent translation initiation (23). More recent work has focused on the regulation of cathepsin L alternative translation. According to the presence of different forms of cathepsin L in distinct subcellular and extracellular compartments, cathepsin L proteins can be initiated from downstream AUG sites (10), omitting the signal peptide that is normally present at the N terminus of lysosomal cathepsin L that routes the protein to the ER during its synthesis (Figure 2) (10, 24-26 Cathepsins were originally identified as proteases that act in the lysosome. Recent work has uncovered nontraditional roles for cathepsins in the extracellular space as well as in the cytosol and nucleus. There is strong evidence that subspecialized and compartmentalized cathepsins participate in many physiologic and pathophysiologic cellular processes, in which they can act as both digestive and regulatory proteases. In this review, we discuss the transcriptional and translational control of cathepsin expression, the regulation of intracellular sorting of cathepsins, and the structural basis of cathepsin activation and inhibition. In particular, we highlight the emerging roles of various cathepsin forms in disease, particularly those of the cardiac and renal systems.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

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Specialized roles for cysteine cathepsins in health and disease

Reiser

Adair²,

Reinheckel³

2010

J. Clin. Invest.

502

403

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“…Importantly, several mouse models of polycystic kidney disease generated by mutating ciliogenic genes show downregulation of p27 Kip1 (Alcalay et al, 2008;Cadieux et al, 2008). Thus, it will be interesting to determine whether dysregulation of cell cycle via p27…”

Section: Kip2mentioning

confidence: 99%

Cell cycle arrest in node cells governs ciliogenesis at the node to break left-right symmetry

2011

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There was an error published in the ePress version of Development 138, 3915-3920 published on 10 August 2011.On p. 3919, in the legend for Fig. 4, asymmetry was incorrectly referred to as symmetry. The correct sentence appears in full below:Subsequently, nodal cilia develop and nodal flow is generated, which triggers the establishment of left-right asymmetry.The replacement ePress article published on 17 August 2011, the online issue and print copy are correct.We apologise to authors and readers for this error.

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“…Moreover, a shift in activity from cathepsin L to D and E was detected. Reduced proteolytic processing of Cux1 by decreased cathepsin L activity is thought to contribute to cyst growth in murine Pkd1 −/− cells (Alcalay et al 2008). Cux1, the murine homolog of human CDP, is a homeobox gene that represses the cyclin kinase inhibitors p21 and p27.…”

Section: Adpkd Biomarkersmentioning

confidence: 99%

Insights into autosomal dominant polycystic kidney disease by quantitative mass spectrometry-based proteomics

Diedrich

Dengjel

2017

Cell Tissue Res

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Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disorder that is caused by mutations in the genes PKD1 and PKD2 encoding polycystin-1 and polycystin-2, respectively. Polycystin-1 and -2 form a complex, interact with several proteins involved in signal transduction and localize to discrete subcellular positions, most importantly the primary cilium. Whereas the causative mutations leading to ADPKD are known, the underlying deregulated cellular pathways are not well understood. In the current review, we introduce state-of-the-art mass spectrometry (MS)-based proteomic techniques and summarize their use in kidney and ADPKD research. Proteomic profiling approaches, the elucidation of ADPKD-relevant proteinprotein interactions and the regulation of posttranslational modifications are included. We also discuss the use of MS-based methods for ADPKD prognosis, diagnosis and disease monitoring by using protein-and peptide-based biomarkers.

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Acceleration of polycystic kidney disease progression in cpk mice carrying a deletion in the homeodomain protein Cux1

Cited by 29 publications

References 72 publications

Specialized roles for cysteine cathepsins in health and disease

Specialized roles for cysteine cathepsins in health and disease

Cell cycle arrest in node cells governs ciliogenesis at the node to break left-right symmetry

Insights into autosomal dominant polycystic kidney disease by quantitative mass spectrometry-based proteomics

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