Functional Defects in Lysosomal Enzymes in Autosomal Dominant Polycystic Kidney Disease (ADPKD): Abnormalities in Synthesis, Molecular Processing, Polarity, and Secretion

Hartz, Patricia A.; Wilson, Patricia D.

doi:10.1006/bmme.1996.2542

Cited by 17 publications

(8 citation statements)

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“…Traditionally three cathepsin H forms are described, including a 41 kDa proform, a 28 kDa mature single-chain form and a twochain mature form consisting of the 22 kDa heavy-chain plus a 6 kDa light-chain of cathepsin H . In addition, unusual cathepsin H molecular forms have been reported for a cancer cell line (Waguri et al, 1995) and for polycystic kidney disease (Hartz and Wilson, 1997). Our Western blot data on cathepsin H protein bands has revealed a cathepsin H protein doublet at 31 and 29 kDa, present in 41/43 (95%) normal colon mucosa samples.…”

Section: Discussionsupporting

confidence: 66%

“…For example, cathepsin H, detected by ELISA, in squamous cell carcinomas of the head and neck, was found to be higher in normal compared to malignant cell extracts (Kos et al, 1995), with high normal cathepsin H concentrations correlating with longer disease-free survival (Budinha et al, 1996). Cathepsin H enzyme activity was also diminished in polycystic kidney disease, a non-cancer condition, characterized by hyperproliferation (Hartz and Wilson, 1997). Still other studies have measured higher cathepsin H gene expression in well differentiated pancreatic cancer cells compared to less differentiated cancer cells (Paciucci et al, 1996).…”

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confidence: 99%

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Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas

Shuja

Cai

et al. 2000

Br J Cancer

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SummaryOur analyses of cathepsin H activity levels and protein forms in human colorectal cancers compared to matched control mucosa support the concept that altered proteinase expression patterns may reflect both cancer stage and site. Cathepsin H-specific activity was significantly increased in colorectal cancers compared to control mucosa (P = 0.003; n = 77). Highest specific activities and cancer/normal ratios (C/N) for activity were measured in Dukes' B and C stage carcinomas, cancers involved in local spread and invasion to lymph nodes. In contrast, cathepsin B and L activities analysed in the same paired extracts had been shown to be most frequently elevated in earlier stage carcinomas (Dukes' A and B), confirming that cathepsin H demonstrates a distinct pattern of expression during colorectal cancer progression. Although cathepsin H activities were most commonly elevated in Dukes' C cancers at all colon sites, both specific activity and C/N ratios were significantly higher for cancers of the left colon compared to other colon locations. A subset of 43 paired extracts analysed on Western blots also revealed consistent changes in cathepsin H protein forms in cancers. Normal mucosa typically showed a strong protein doublet at 31 and 29 kDa while cancers demonstrated decreased expression or total loss of the 31 kDa protein (90% of cases), equal or increased expression of the 29-kDa protein (67% of cases) and the new appearance or up-regulation of a cathepsin H band at 22 kDa (78% of cases). C/N ratios for cathepsin H enzyme activity correlated significantly with C/N ratios for the 29 kDa mature single-chain protein form (P < 0.001), with increased activity most commonly associated with elevated expression of 29-kDa cathepsin H but also with up-regulation of the 22-kDa band, suggesting a shift to more fully processed, mature active cathepsin H protein forms in cancers. Changes in cathepsin H expression were also detected by immunohistochemistry as elevated cathepsin H staining in tumour epithelial cells.

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Section: Discussionsupporting

confidence: 66%

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confidence: 99%

Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas

Shuja

Cai

et al. 2000

Br J Cancer

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“…The same authors also observed cathepsin B and dipeptidylpeptidase activity in the lysosomes of the proximal tubules and the small lysosomes of the distal tubule (28). The activity of cathepsins D (20,43), B, H, and L (20) have also been demonstrated in collecting tubules.…”

Section: Discussionmentioning

confidence: 74%

“…In mice, cathepsin D is most abundant in the cortical collecting tubule, and cathepsins B and H are located in the proximal convoluted tubule (43). High activities of ␤-galactosidase, ␤-hexosaminidase, and cathepsins B, H, L, and D are also present in human kidney and in confluent primary cultures of epithelia from proximal, collecting, and thick ascending limb tubules (20). Kugler et al (28) noted that the human kidney is well equipped with membrane-bound and lysosomal peptidases, principally in the proximal tubules, whose brush borders contain high levels of aminopeptidase A, aminopeptidase M, ␥-glutamyl transferase, and dipeptidylpeptidase IV.…”

Section: Discussionmentioning

confidence: 99%

Intracrystalline urinary proteins facilitate degradation and dissolution of calcium oxalate crystals in cultured renal cells

Grover¹,

Thurgood²,

Fleming³

et al. 2008

American Journal of Physiology-Renal Physiology

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134: 5-14, 2001. The aim of this investigation was to determine the effect of increasing concentrations of intracrystalline protein on the rate of CaOx crystal dissolution in Madin-Darby canine kidney (MDCKII) cells. Crystal matrix extract (CME) was isolated from urinary CaOx monohydrate (COM) crystals. Cold and [ 14 C]oxalate-labeled COM crystals were precipitated from ultrafiltered urine containing 0 -5 mg/l CME. Crystal surface area was estimated from scanning electron micrographs, and synchrotron X-ray diffraction was used to determine nonuniform strain and crystallite size. Radiolabeled crystals were added to MDCKII cells and crystal dissolution, expressed as radioactive label released into the medium, was measured. Increasing CME content did not significantly alter crystal surface area. However, nonuniform strain increased and crystallite size decreased in a dose-response manner, both reaching saturation at a CME concentration of 3 mg/ and demonstrating unequivocally the inclusion of increasing quantities of proteins in the crystals. This was confirmed by Western blotting. Crystal dissolution also followed saturation kinetics, increasing proportionally with final CME concentration and reaching a plateau at a concentration of ϳ2 mg/l. These findings were complemented by field emission scanning electron microscopy, which showed that crystal degradation also increased relative to CME concentration. Intracrystalline proteins enhance degradation and dissolution of CaOx crystals and thus may constitute a natural defense against urolithiasis. The findings have significant ramifications in biomineral metabolism and pathogenesis of renal stones. nephrocalcinosis; urolithiasis THE PATHOGENESIS OF RENAL calculi requires the sequential combination of two processes, namely, the nucleation of crystals and their retention within the kidney. While crystal nucleation requires supersaturation of urine with calcium oxalate (CaOx), renal crystal trapping has been explained by either the "free particle" or "fixed particle" theory. Although both these theories appear equally plausible (26), current consensus favors a fixed particle mechanism. This view is supported by the results of studies performed in the early 1990s, which demonstrated for the first time that CaOx crystals irreversibly adhere to and are phagocytosed by cultured renal epithelial cells (35,39). These findings introduced a new paradigm to urolithiasis research because they validated the credibility of using this experimental approach to examine and manipulate factors affecting the regulation of crystal retention, which had not previously been possible. Consequently, there followed a series of reports investigating factors affecting interactions between CaOx monohydrate (COM) crystals and renal cells (reviewed in Refs. 30 and 38). Those studies showed that COM crystals, which are the predominant form of CaOx occurring in human kidney stones (41), are highly membranolytic (55), and also that their adherence to renal epithelial cells is very rapid, concentration ...

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“…d: In contrast, cathepsin-L is reduced in the nuclei of cystic kidneys from E18.5 Pkd1 null mice (arrowheads). Cux1 (p200) represses p21 and p27 promoter activity in a concentration-dependent manner (10,25). The decreased expression of p21 and p27 in the cystic kidneys expressing the Cux1⌬CR1 protein suggests that this protein can function similar to the Cux1 (p200) protein.…”

Section: Discussionmentioning

confidence: 99%

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

Alcalay

Sharma²,

Vassmer³

et al. 2008

American Journal of Physiology-Renal Physiology

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Polycystic kidney diseases (PKD) are inherited as autosomal dominant (ADPKD) or autosomal recessive (ARPKD) traits and are characterized by progressive enlargement of renal cysts. Aberrant cell proliferation is a key feature in the progression of PKD. Cux1 is a homeobox gene that is related to Drosophila cut and is the murine homolog of human CDP (CCAAT Displacement Protein). Cux1 represses the cyclin kinase inhibitors p21 and p27, and transgenic mice ectopically expressing Cux1 develop renal hyperplasia. However, Cux1 transgenic mice do not develop PKD. Here, we show that a 246 amino acid deletion in Cux1 accelerates PKD progression in cpk mice. Cystic kidneys isolated from 10-day-old cpk/Cux1 double mutant mice were significantly larger than kidneys from 10-day-old cpk mice. Moreover, renal function was significantly reduced in the Cux1 mutant cpk mice, compared with cpk mice. The mutant Cux1 protein was ectopically expressed in cyst-lining cells, where expression corresponded to increased cell proliferation and apoptosis, and a decrease in expression of the cyclin kinase inhibitors p27 and p21. While the mutant Cux1 protein altered PKD progression, kidneys from mice carrying the mutant Cux1 protein alone were phenotypically normal, suggesting the Cux1 mutation modifies PKD progression in cpk mice. During cell cycle progression, Cux1 is proteolytically processed by a nuclear isoform of the cysteine protease cathepsin-L. Analysis of the deleted sequences reveals that a cathepsin-L processing site in Cux1 is deleted. Moreover, nuclear cathepsin-L is significantly reduced in both human ADPKD cells and in Pkd1 null kidneys, corresponding to increased levels of Cux1 protein in the cystic cells and kidneys. These results suggest a mechanism in which reduced Cux1 processing by cathepsin-L results in the accumulation of Cux1, downregulation of p21/p27, and increased cell proliferation in PKD.

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Functional Defects in Lysosomal Enzymes in Autosomal Dominant Polycystic Kidney Disease (ADPKD): Abnormalities in Synthesis, Molecular Processing, Polarity, and Secretion

Cited by 17 publications

References 0 publications

Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas

Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas

Intracrystalline urinary proteins facilitate degradation and dissolution of calcium oxalate crystals in cultured renal cells

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

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