Identification of two new exons and multiple transcription start points in the 5′-untranslated region of the human cathepsin-B-encoding gene

Berquin, Isabelle M.; Cao, Lequn; Fong, Dunne; Sloane, Bonnie F.

doi:10.1016/0378-1119(95)00072-e

Cited by 74 publications

(53 citation statements)

References 15 publications

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“…Therefore, it was initially classified as a housekeeping gene (Berquin et al, 1995). However, further investigations revealed that this protease is regulated at multiple levels, including transcription, post-transcriptional processing, translation, and trafficking by endogenous compounds such as transforming growth factor-␤ (Gerber et al, 2000), interferon-␥ (Li et al, 1998), and granulocyte/macrophage colony-stimulating factor (Ward et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

“…In this model, cathepsin B is significantly involved in the onset of pancreatitis (Halangk et al, 2000) as well as in tumor necrosis factor-␣-mediated apoptosis of hepatocytes, hepatic inflammation, and fibrogenesis (Guicciardi et al, 2001;Canbay et al, 2003). In different cancer types, cathepsin B has been shown to be elevated, and its cellular trafficking is frequently altered in malignant cells, resulting in an increased secretion of precursor and active forms of the enzyme (Berquin et al, 1995). In addition, studies using cathepsin B antisense techniques revealed a pivotal role of cathepsin B for invasion and motility of glioblastoma (Mohanam et al, 2001) and osteosarcoma cells (Krueger et al, 1999).…”

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confidence: 99%

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Nuclear Factor-κB Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells

Bien

Grätz²,

Sperker³

et al. 2004

Mol Pharmacol

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Anthracyclines such as doxorubicin remain among the most effective agents for the treatment of solid tumors and hematological malignancies. To overcome dose-limiting side effects like cardiotoxicity, an intensive effort has been undertaken to develop promising doxorubicin prodrugs that are specifically activated at the tumor site. One approach is the application of peptide prodrugs of doxorubicin. The enzyme cathepsin B catalyzes the activation of these prodrugs, and hence, the regulation of cathepsin B by antitumor agents could influence the efficacy of peptide prodrugs using this protease. In the present investigation, the effects of doxorubicin on cathepsin B expression in the human cervix carcinoma cell line HeLa were examined. Exposure to doxorubicin induced a time-and dose-dependent up-regulation of cathepsin B expression on mRNA, protein, and activity levels. In the cathepsin B gene promoter region, a potential nuclear factor B (NF-B) binding site could be identified. Pretreatment of HeLa cells with specific NF-B inhibitors abrogated the induction of cathepsin B expression. Doxorubicin-induced degradation of the inhibitory protein IB could be prevented by pretreatment with a specific proteasome inhibitor, resulting in a significant reduction of the doxorubicininduced cathepsin B expression. Finally, binding of NF-B subunits p50 and p65 to the NF-B binding site in the cathepsin B gene promoter region could be demonstrated by electrophoretic mobility shift assay. In summary, our data clearly indicate that doxorubicin induces cathepsin B expression and activity via NF-B. These findings contribute to a better understanding of tumor targeting with peptide prodrugs and help to define a possible mechanism of doxorubicin toxicity in tumor cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nuclear Factor-κB Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells

Bien

Grätz²,

Sperker³

et al. 2004

Mol Pharmacol

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“…The shorter message, which was more active in an in vitro translation assay, is the predominant form in many human tumors (14). Remarkably, some human tumors also contain transcripts that are additionally missing exon 3 which encodes the signal peptide and part of the inhibitory propeptide (14,17). In Fig.…”

Section: Transcripts Missing Exons 2 and 3 From A375 Human Melanoma Cmentioning

confidence: 99%

“…Some human tumors also contain cathepsin B-related transcripts that differ in their 5Ј-coding region (14,17). These appear to arise from the skipping of exons 2 and 3 during splicing of the pre-mRNA (14), and from transcription initiation in exon 4 (17).…”

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confidence: 99%

In VivoExpression of an Alternatively Spliced Human Tumor Message That Encodes a Truncated Form of Cathepsin B

Mehtani¹,

Gong²,

Panella³

et al. 1998

Journal of Biological Chemistry

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Cathepsin B is a lysosomal cysteine protease whose increased expression is believed to be linked to the malignant progression of tumors. Alternative splicing and the use of alternative transcription initiation sites in humans produce cathepsin B mRNAs that differ in their 5-and 3-untranslated ends. Some human tumors also contain cathepsin B-related transcripts that lack exon 3 which encodes the N-terminal signal peptide and 34 of the 62-amino acid inhibitory propeptide. In this study we show that one such transcript, CB(؊2,3), which is missing exons 2 and 3, is likely to be a functional message in tumors. Thus, CB(؊2,3) was found to be otherwise complete, containing the remainder of the cathepsin B coding sequence and the part of the 3-untranslated region that is common to all previously characterized cathepsin B mRNAs in humans. Its in vitro translation product can be folded to produce enzymatic activity against the cathepsin B-specific substrate, N ␣ -benzyloxycarbonyl-L-Arg-L-Arg-4-methylcoumaryl-7-amide. Endogenous CB(؊2,3) from the metastatic human melanoma cell line, A375M, co-sediments with polysomes, indicating that it engages the eukaryotic translation machinery in these cells. Epitope-tagged forms of the truncated cathepsin B from CB(؊2,3) are produced in amounts comparable to the normal protein after transient transfection into COS cells. Immunofluorescence microscopy and subcellular fractionation show this novel tumor form of cathepsin B to be associated with nuclei and other membranous organelles, where it is likely to be bound to the cytoplasmic face of the membranes. This subcellular distribution was different from the lysosomal pattern shown by the epitope-tagged, full-length cathepsin B in COS cells. These results indicate that the message missing exons 2 and 3 is likely to be translated into a catalytically active enzyme, and that alternative splicing (exon skipping) could contribute to the aberrant intracellular trafficking of cathepsin B that is observed in some human cancers.Cathepsin B is a lysosomal cysteine protease whose expression and trafficking are frequently altered in transformed and malignant cells (1). Both its association with the plasma membrane and its secretion have been linked to the increased capacity of human and rodent tumors to invade and metastasize (2-5). The association of cathepsin B with cell fractions containing plasma membrane-derived vesicles and endosomes was found to increase after transfection of a human breast epithelial cell line with the c-Ha-ras oncogene (6). Cathepsin B has been detected in nuclei from human ectocervical tumors and in basal and columnar cells of the normal and hyperplastic prostate (7,8). In human lung tumor cell lines cathepsin B activity was also localized to the endoplasmic reticulum, nuclear membrane, and plasma membrane (9). Forms of cathepsin B greater in size and stability than the mature, lysosomal form have been observed in tumors from humans and animals or in media conditioned by them (10 -13). At present, many of these findings ...

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“…Transcript variants are tumour cells for cathepsins B and L, arising from the use of alternative promoters 34,35 and alternative splicing 36,37 . In these cells shorter transcripts are formed which are easily translated and hence lead to their over expression 38,39 .…”

Section: Up Regulation During Cancermentioning

confidence: 99%

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Identification of two new exons and multiple transcription start points in the 5′-untranslated region of the human cathepsin-B-encoding gene

Cited by 74 publications

References 15 publications

Nuclear Factor-κB Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells

Nuclear Factor-κB Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells

In VivoExpression of an Alternatively Spliced Human Tumor Message That Encodes a Truncated Form of Cathepsin B

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