X-ray Structure of Two Crystalline Forms of aStreptomycete Ribonuclease with Cytotoxic Activity

Ševčı́k, Jozef; Urbanikova, L.; Leland, Peter A.; Raines, Ronald T.

doi:10.1074/jbc.m208425200

Cited by 43 publications

(32 citation statements)

References 57 publications

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“…Its crystallographic structure, also in complexes with ligands was determined (Sevcik et al, 1991, 1993). The structure of its isoenzyme Sa3 was also refined (Sevcik et al, 2002). …”

Section: Binase and Other Microbial Ribonucleasesmentioning

confidence: 99%

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Ribonucleases as potential modalities in anticancer therapy

Ardelt

Darzynkiewicz

2009

European Journal of Pharmacology

112

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Antitumor ribonucleases are small (10–28 kDa) basic proteins. They were found among members of both, ribonuclease A and T1 superfamilies. Their cytotoxic properties are conferred by enzymatic activity, i.e., the ability to catalyze cleavages of phosphodiester bonds in RNA. They bind to negatively charged cell membrane, enter cells by endocytosis and translocate to cytosol where they evade mammalian protein ribonuclease inhibitor and degrade RNA. Here, we discuss structures, functions and mechanisms of antitumor activity of several cytotoxic ribonucleases with particular emphasis to the amphibian Onconase, the only enzyme of this class that reached clinical trials. Onconase is the smallest, very stable, less catalytically efficient and more cytotoxic than most RNase A homologues. Its cytostatic, cytotoxic and anticancer effects were extensively studied. It targets tRNA, rRNA, mRNA as well as the non-coding RNA (microRNAs). Numerous cancer lines are sensitive to Onconase; their treatment with 10 – 100 nM enzyme leads to suppression of cell cycle progression, predominantly through G1, followed by apoptosis or cell senescence. Onconase also has anticancer properties in animal models. Many effects of this enzyme are consistent with the microRNAs, one of its critical targets. Onconase sensitizes cells to a variety of anticancer modalities and this property is of particular interest, suggesting its application as an adjunct to chemotherapy or radiotherapy in treatment of different tumors. Cytotoxic RNases as exemplified by Onconase represent a new class of antitumor agents, with an entirely different mechanism of action than the drugs currently used in the clinic. Further studies on animal models including human tumors grafted on severe combined immunodefficient (SCID) mice and clinical trials are needed to explore clinical potential of cytotoxic RNases.

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“…Its crystallographic structure, also in complexes with ligands was determined (Sevcik et al, 1991, 1993). The structure of its isoenzyme Sa3 was also refined (Sevcik et al, 2002). …”

Section: Binase and Other Microbial Ribonucleasesmentioning

confidence: 99%

“…They are not affected by mammalian RNase inhibitor (Sevcik et al, 2002). Both enzymes are guanine-specific; the guanine biding site was well characterized by crystallography.…”

Section: Binase and Other Microbial Ribonucleasesmentioning

confidence: 99%

Ribonucleases as potential modalities in anticancer therapy

Ardelt

Darzynkiewicz

2009

European Journal of Pharmacology

112

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“…Antitumour potential is known since long ago for exogenous ribonucleases (RNases) derived from fungi (streptomycete ribonuclease [13]), bacteria (binase [14]–[16]), reptiles (onconase [17]–[19], cSBL and jSBL RNases [20]), and mammals [21]–[24]. A number of investigations were devoted to the direct cytotoxic effect of natural ribonucleases on tumour cells associated with intracellular coding and non-coding RNA cleavage [25]–[30].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA Drop in the Bloodstream and MicroRNA Boost in the Tumour Caused by Treatment with Ribonuclease A Leads to an Attenuation of Tumour Malignancy

et al. 2013

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Novel data showing an important role of microRNAs in mediating tumour progression opened a new field of possible molecular targets for cytotoxic ribonucleases. Recently, antitumour and antimetastatic activities of pancreatic ribonuclease A were demonstrated and here genome-wide profiles of microRNAs in the tumour and blood of mice bearing Lewis lung carcinoma after treatment with RNase A were analysed by high-throughput Sequencing by Oligonucleotide Ligation and Detection (SOLiD™) sequencing technology. Sequencing data showed that RNase A therapy resulted in the boost of 116 microRNAs in tumour tissue and a significant drop of 137 microRNAs in the bloodstream that were confirmed by qPCR. The microRNA boost in the tumour was accompanied by the overexpression of microRNA processing genes: RNASEN (Drosha), xpo5, dicer1, and eif2c2 (Ago2). Ribonuclease activity of RNase A was shown to be crucial for the activation of both microRNA synthesis and expression of the microRNA processing genes. In the tumour tissue, RNase A caused the upregulation of both oncomirs and tumour-suppressor microRNAs, including microRNAs of the let-7 family, known to negatively regulate tumour progression. Our results suggest that the alteration of microRNA signature caused by RNase A treatment leads to the attenuation of tumour malignancy.

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“…[1][2][3][4][5] The antitumor activity was shown for BS-RNase from bovine seminal, [6][7][8][9] onconase from oocytes of Rana pipiens, [10][11][12] bovine pancreatic RNase A, 13 cSBL and jSBL RNases from Rana catesbeiana and Rana japonica, 14 microbial RNases [15][16][17] and conjugates of RNases with various molecules. [18][19][20] One of the properties that are important for potential therapeutic application of RNases is their ability to induce cancer cell death by apoptosis.…”

Section: Introductionmentioning

confidence: 99%