Cathepsins B and L and their inhibitors stefin B and cystatin C as markers for malignant progression of benign meningiomas

Trinkaus, Miha; Vranic, Andrej; Dolenc, Vinko V.; Lah, Tamara T.

doi:10.5301/jbm.2008.1564

Cited by 13 publications

(7 citation statements)

References 26 publications

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“…In addition, while the data presented in the current report are suggestive of a key role for Cat L in PGRN processing in neurons, additional studies performed in Cat L knockout animals will be an intriguing new research direction to further clarify the mechanisms by which PGRN is processed within neurons in the brain. The elucidation of consequences on PGRN processing following altered expression of the endogenous cathepsin L inhibitors, cystatin C and M/E [37, 38], will also be an interesting research direction for future studies, and may represent a novel approach to therapeutically modulate the PGRN/granulin axis in vivo. In conclusion, as Cat L-mediated processing of PGRN in the lysosome may be of critical importance in the neuropathobiology of FTLD-GRN, the current findings provide a first step in understanding the physiological importance of Cat L processing of PGRN in neurons.…”

Section: Discussionmentioning

confidence: 99%

The lysosomal protein cathepsin L is a progranulin protease

Lee

Stankowski

Chew

et al. 2017

Mol Neurodegeneration

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Haploinsufficiency of GRN, the gene encoding progranulin (PGRN), causes frontotemporal lobar degeneration (FTLD), the second most common cause of early-onset dementia. Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Here we show that the lysosomal cysteine protease cathepsin L (Cat L) can mediate the proteolytic cleavage of intracellular PGRN into poly-granulin and granulin fragments. Further, PGRN and Cat L co-localize in lysosomes of HEK293 cells, iPSC-derived neurons and human cortical neurons from human postmortem tissue. These data identify Cat L as a key intracellular lysosomal PGRN protease, and provides an intriguing new link between lysosomal dysfunction and FTLD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0196-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The lysosomal protein cathepsin L is a progranulin protease

Lee

Stankowski

Chew

et al. 2017

Mol Neurodegeneration

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“…Cathepsin B is also inhibited by cystatin B (stefin B) and cystatin C . Low mRNA and protein levels of cystatin B are detected in atypical as compared to benign meningioma along with high protein levels of cathepsin B . Changes in the expression of cystatins A and E/M have also been observed in advanced stage prostate and breast cancers, respectively .…”

Section: Regulation Of Cathepsin Bmentioning

confidence: 99%

Cathepsin B: Multiple roles in cancer

Aggarwal

Sloane

2014

Proteomics Clinical Apps

326

236

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Proteases, including intracellular proteases, play roles at many different stages of malignant progression. Our focus here is cathepsin B, a lysosomal cysteine cathepsin. High levels of cathepsin B are found in a wide variety of human cancers, levels that often induce secretion and association of cathepsin B with the tumor cell membrane. In experimental models, such as transgenic models of murine pancreatic and mammary carcinomas, causal roles for cathepsin B have been demonstrated in initiation, growth/tumor cell proliferation, angiogenesis, invasion, and metastasis. Tumor growth in transgenic models is promoted by cathepsin B in tumor-associated cells, for example, tumor-associated macrophages, as well as in tumor cells. In transgenic models, the absence of cathepsin B has been associated with enhanced apoptosis, yet cathepsin B also has been shown to contribute to apoptosis. Cathepsin B is part of a proteolytic pathway identified in xenograft models of human glioma; targeting only cathepsin B in these tumors is less effective than targeting cathepsin B in combination with other proteases or protease receptors. Understanding the mechanisms responsible for increased expression of cathepsin B in tumors and association of cathepsin B with tumor cell membranes is needed to determine whether targeting cathepsin B could be of therapeutic benefit.

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“…Cystatin A and B and cathepsins (in particular cathepsin L and B) have been implicated in the positive/negative progression of cancer, maybe due to the unbalance between the proteases and their inhibitors [70][71][72][73][74][75][76][77] and to cystatin involvement in cell growth. In particular, CSTB has been proposed as a prognostic marker in a number of tumours.…”

Section: Overexpression Of Cystatinsmentioning

confidence: 99%

“…In particular, CSTB has been proposed as a prognostic marker in a number of tumours. Increased levels of CSTB are often associated to a decrease of relapse risk [11,[71][72][73][74][75][76][77][78][79]. The only exception, so far described, is colorectal cancer where high levels of extracellular cysteine proteinase inhibitors indicate a poor prognosis [72].…”

Section: Overexpression Of Cystatinsmentioning

confidence: 99%

Cystatin B and its EPM1 mutants are polymeric and aggregate prone in vivo

Cipollini

Riccio

Giaimo

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Progressive myoclonus epilepsy type 1 (EPM1) is a neurodegenerative disease correlating with mutations of the cystatin B gene. Cystatin B is described as a monomeric protein with antiprotease function. This work shows that, in vivo, cystatin B has a polymeric structure, highly resistant to SDS, urea, boiling and sensitive to reducing agents and alkaline pH. Hydrogen peroxide increases the polymeric structure of the protein. Mass spectrometry analysis shows that the only component of the polymers is cystatin B. EPM1 mutants of cystatin B transfected in cultured cells are also polymeric. The banding pattern generated by a cysteine-minus mutant is different from that of the wild-type protein as it contains only monomers, dimers and some very high MW bands while misses components of MW intermediate between 25 and 250 kDa. Overexpression of wild-type or EPM1 mutants of cystatin B in neuroblastoma cells generates cytoplasmic aggregates. The cysteine-minus mutant is less prone to the formation of inclusion bodies. We conclude that cystatin B in vivo has a polymeric structure sensitive to the redox environment and that overexpression of the protein generates aggregates. This work describes a protein with a physiological role characterized by highly stable polymers prone to aggregate formation in vivo.

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Cathepsins B and L and their inhibitors stefin B and cystatin C as markers for malignant progression of benign meningiomas

Cited by 13 publications

References 26 publications

The lysosomal protein cathepsin L is a progranulin protease

The lysosomal protein cathepsin L is a progranulin protease

Cathepsin B: Multiple roles in cancer

Cystatin B and its EPM1 mutants are polymeric and aggregate prone in vivo

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