Refined 1·7 Å X-ray crystallographic structure of P-30 protein, an amphibian ribonuclease with anti-tumor activity

Mosimann, S.C.; Ardelt, Wojciech; James, Michael N.G.

doi:10.1016/0022-2836(94)90017-5

Cited by 130 publications

(158 citation statements)

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“…The best characterized is Onconase (Onc), a basic and remarkably stable ribonuclease of approximately 12,000 MW . [5][6][7][8][9][10] Onc is cytostatic and cytotoxic to tumor cell lines of different lineage, [11][12][13][14][15] inhibits tumor growth in mice, 16,17 and under the trade name of ONCONASE® its antitumor properties are being currently evaluated in Phase III clinical trials. 18 The mechanism by which Onc exerts cytostatic and cytotoxic activity is not well understood.…”

Section: Cytotoxic Ribonucleases (Crs)-interactions With the Target Cmentioning

confidence: 99%

Cytotoxic Ribonucleases and RNA Interference (RNAi)

Ardelt¹,

Ardelt²,

Darżynkiewicz³

2003

Cell Cycle

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Section: Cytotoxic Ribonucleases (Crs)-interactions With the Target Cmentioning

confidence: 99%

Cytotoxic Ribonucleases and RNA Interference (RNAi)

Ardelt¹,

Ardelt²,

Darżynkiewicz³

2003

Cell Cycle

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“…2,3 This protein is homologous to members of the pancreatic RNase superfamily and, although considerably less active than RNase A, also possesses ribonucleolytic activity. 2,4,5 Onconase shows antiproliferative activity in vitro, suppressing proliferation of tumor cell lines of different lineage including hematological tumors.…”

Section: Introductionmentioning

confidence: 99%

G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A, p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation

Juan

Ardelt

et al. 1998

Leukemia

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Onconase is a 12 kDa protein homologous to pancreatic RNase A isolated from amphibian oocytes which shows cytostatic and cytotoxic activity in vitro, inhibits growth of tumors in mice and is in phase III clinical trials. The present study was aimed to reveal mechanisms by which onconase perturbs the cell cycle progression. Human histiocytic lymphoma U937 cells were treated with onconase and expression of cyclins D3 and E, as well as of the cyclin-dependent kinase inhibitors (CKIs) p16 , the events which may prevent phosphorylation of pRb during G 0/1 and result in cell arrest at the restriction point controlled by Cdk4/6 and D type cyclins.

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“…Onconase (ONC) from Rana pipiens is cytotoxic (10) and cytostatic to several tumor lines and is currently in phase III clinical trials for the treatment of malignant mesothelioma (8,11,12). ONC shares 30% of identity with the sequence of RNase A, and its three-dimensional structure exhibits a highly conserved ribonuclease-like topology (13), which comprises a characteristic V-shaped ␤-sheet motif surrounded by three ␣-helices. Differences are mainly localized in the loop regions, which are significantly shorter in ONC, and at the C terminus where a disulfide bond, unique to amphibian ribonucleases, tethers the C-terminal residue Cys 104 to Cys 87 located in one strand of the ␤-sheet (13).…”

mentioning

confidence: 99%

“…ONC shares 30% of identity with the sequence of RNase A, and its three-dimensional structure exhibits a highly conserved ribonuclease-like topology (13), which comprises a characteristic V-shaped ␤-sheet motif surrounded by three ␣-helices. Differences are mainly localized in the loop regions, which are significantly shorter in ONC, and at the C terminus where a disulfide bond, unique to amphibian ribonucleases, tethers the C-terminal residue Cys 104 to Cys 87 located in one strand of the ␤-sheet (13). Another distinct property of ONC is the presence of an N-terminal pyroglutamate (Pyr 1 ), which folds back against the N-terminal helix (13).…”

mentioning

confidence: 99%

The Importance of Dynamic Effects on the Enzyme Activity

Merlino

Mazzarella

Carannante

et al. 2005

Journal of Biological Chemistry

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Onconase (ONC), a member of the RNase A superfamily extracted from oocytes of Rana pipiens, is an effective cancer killer. It is currently used in treatment of various forms of cancer. ONC antitumor properties depend on its ribonucleolytic activity that is low in comparison with other members of the superfamily. The most damaging side effect from Onconase treatment is renal toxicity, which seems to be caused by the unusual stability of the enzyme. Therefore, mutants with reduced thermal stability and/or increased catalytic activity may have significant implications for human cancer chemotherapy. In this context, we have determined the crystal structures of two Onconase mutants (M23L-ONC and C87S,des103-104-ONC) and performed molecular dynamic simulations of ONC and C87S,des103-104-ONC with the aim of explaining on structural grounds the modifications of the activity and thermal stability of the mutants. The results also provide the molecular bases to explain the lower catalytic activity of Onconase compared with RNase A and the unusually high thermal stability of the amphibian enzyme.Ribonucleases are widely found in living organisms and have been proposed to function in RNA metabolism and gene expression (1). Several ribonucleases have been isolated from organs of various animals and have been well characterized. Bovine pancreatic ribonuclease (RNase A) 1 is the most studied member of the family (2). It has been used as a model for the study of the fundamental aspects of protein structure and function (2, 3). Several members of the RNase A superfamily exhibit additional biological functions in connection with their intrinsic ribonucleolytic activities (4, 5). In humans, eosinophil-derived neurotoxin and eosinophil cationic protein (6) exert neurotoxicity as well as antiparasitic activity (7). Bovine seminal ribonuclease (BS-RNase) has been found to induce apoptosis of human thyroid carcinoma cell lines (8, 9). Onconase (ONC) from Rana pipiens is cytotoxic (10) and cytostatic to several tumor lines and is currently in phase III clinical trials for the treatment of malignant mesothelioma (8,11,12). ONC shares 30% of identity with the sequence of RNase A, and its three-dimensional structure exhibits a highly conserved ribonuclease-like topology (13), which comprises a characteristic V-shaped ␤-sheet motif surrounded by three ␣-helices. Differences are mainly localized in the loop regions, which are significantly shorter in ONC, and at the C terminus where a disulfide bond, unique to amphibian ribonucleases, tethers the C-terminal residue Cys 104 to Cys 87 located in one strand of the ␤-sheet (13). Another distinct property of ONC is the presence of an N-terminal pyroglutamate (Pyr 1 ), which folds back against the N-terminal helix (13). The overall active site architecture closely resembles that of RNase A and includes His 10 , Lys 31 , and His 97 , which form the catalytic triad corresponding to His 12 , Lys 41 , and His 119 , respectively, of the pancreatic enzyme. Despite this similarity and the activating effe...

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Refined 1·7 Å X-ray crystallographic structure of P-30 protein, an amphibian ribonuclease with anti-tumor activity

Cited by 130 publications

References 31 publications

Cytotoxic Ribonucleases and RNA Interference (RNAi)

Cytotoxic Ribonucleases and RNA Interference (RNAi)

G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A, p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation

The Importance of Dynamic Effects on the Enzyme Activity

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