Cathepsin B Regulates the Intrinsic Angiogenic Threshold of Endothelial Cells

Venkatakrishnan, Annapurna; Kazlauskas, Andrius

doi:10.1091/mbc.e04-11-1029

Cited by 116 publications

(107 citation statements)

References 53 publications

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“…Two-dimensional tube assays were performed as previously described (44). Briefly, CECs (6 ϫ 10 5 ) were plated between two layers of collagen gel in endothelial basal medium (with 0.5% serum [Lonza]).…”

Section: Methodsmentioning

confidence: 99%

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular agerelated macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD. Single nucleotide polymorphisms (SNPs) that fall within the coding region have the potential to alter the amino acid sequence of a gene's product and therefore can serve as a Rosetta stone for understanding the pathogenesis of human disorders (1, 2). A curiosity that emerged from human genome-wide association studies is that exonic SNPs that do not alter the amino acid sequence of the protein product (i.e., SNPs that are synonymous) are as common as SNPs that do (i.e., SNPs that are nonsynonymous) (3). Furthermore, some of the disease-associated synonymous SNPs constitute the molecular underpinnings of pathology, meaning that they are enriched in affected human subjects and alter the gene product. For the majority (95%) of disease-associated synonymous SNPs, aberrant gene products were attributed to unstable mRNA transcripts with a reduced half-life or mutations in splice sites that resulted in exon skipping (4, 5). In other cases, synonymous SNPs caused translational defects independently of mRNA splicing errors (6-9).A parsimonious mechanism by which synonymous SNPs impact the integrity of protein products involves the alteration of codon usage. In vivo, folding of nascent proteins proceeds cotranslationally (10, 11) and is influenced by the rate of ribosome transit through the mRNA template. What distinguishes synonymous codons that encode a given degenerate amino acid is the abundance of their corresponding tRNA, which is lower for infrequently used codons than for frequently used codons (12, 13). Consequently, codon frequency can influence the rate of translation. Of note, codon bias has been widely described in prokaryotes and single-celled eukaryotes but less extensively in complex eukaryotes.In humans, correlations between optimum codon usage and either protein expression...

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Section: Methodsmentioning

confidence: 99%

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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“…A c c e p t e d M a n u s c r i p t Cathepsin B, a lysosomal cysteine protease, regulates both pro-and anti-angiogenic factors suggesting that it may be a contributor to the "angiogenic switch" of endothelial cells (Im et al, 2005). Lack of cathepsin B reduces angiogenesis in a mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2) crossed with cathepsin B-null mice (Gocheva et al, 2006).…”

Section: Proteolytic Systemsmentioning

confidence: 99%

Angiogenesis and development of adipose tissue

Christiaens

Lijnen

2010

Molecular and Cellular Endocrinology

195

159

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“…Because cystatin C is the primary inhibitor of the cysteine proteases (cathepsins B, L, H, and S), both the inhibitor and one or more of the cathepsins are functionally implicated in the pathogenesis of AMD. Many functions have been identified for this class of cathepsins including increasing the invasiveness of endothelial cells (Im, et al, 2005), and participating in TNF stimulated apoptosis (Caruso, et al, 2006) These same processes are also observed in the pathogenesis of AMD.…”

Section: Introductionmentioning

confidence: 99%

Regulation of cysteine cathepsin expression by oxidative stress in the retinal pigment epithelium/choroid of the mouse

Alizadeh

Smit-McBride

Oltjen

et al. 2006

Experimental Eye Research

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Cystatin C is the major inhibitor of the cysteine cathepsins. Polymorphisms in the cystatin C gene have recently been associated with the risk of developing Age-related Macular Degeneration (AMD). Oxidative stress is also thought to play a key role in the pathogenesis of AMD. We surveyed the retinal pigment epithelium (RPE) and choroid of the C57BL/6J mouse for the expression of the cysteine cathepsins under normoxic and hyperoxic (75% O 2 ) conditions. Microarray analysis of RPE/ choroid mRNA revealed the expression of cathepsins B and L, as well as cystatin C under all experimental conditions. The microarray results were confirmed by real-time quantitative polymerase chain reaction (PCR). Localization of the mRNA species for cystatin C and cathepsin B, as well as, localization of protein species for cystatin C, cathepsin B and L were performed to evaluate the tissue distribution of these species.Our results indicate that cystatin C is largely synthesized in the RPE and secreted from the basal side. Cathepsin B is the major cysteine protease in the RPE and choroid. The expression of all mRNAs and proteins was elevated by exposure to oxidative stress.

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Cathepsin B Regulates the Intrinsic Angiogenic Threshold of Endothelial Cells

Cited by 116 publications

References 53 publications

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Angiogenesis and development of adipose tissue

Regulation of cysteine cathepsin expression by oxidative stress in the retinal pigment epithelium/choroid of the mouse

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