Toxicity of an antitumor ribonuclease to Purkinje neurons

Newton, D.J.; Walbridge, Stuart; Mikulski, SM; Ardelt, Wojciech; Shogen, Kuslima; Ackerman, S.J.; Rybak, Susanna M.; Rj, Youle

doi:10.1523/jneurosci.14-02-00538.1994

Cited by 63 publications

(44 citation statements)

References 35 publications

(31 reference statements)

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“…Chemical inactivation on RNase activity of onconase, EDN, and ECP by iodoacetate reduced the cytotoxicity/neurotoxicity of these proteins. These results indicate that RNase activity is essential to induce cytotoxic or neurotoxic action (9,11,24). However, two single base pair mutations (K35R, H128D) were introduced in human recombinant ECP to convert RNase inactivity and did not have discernible effect on antibacterial activity (25).…”

Section: Amino Acid Sequence and Dna Sequence Homologies In Rnase Supmentioning

confidence: 97%

The Rana catesbeiana rcr Gene Encoding a Cytotoxic Ribonuclease

Huang¹,

Wang²,

Leu³

et al. 1998

Journal of Biological Chemistry

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Rana catesbeiana ribonuclease (RC-RNase) is a pyrimidine-guanine sequence-specific ribonuclease found in R. catesbeiana (bullfrog) oocytes. It possesses both ribonuclease activity and cytotoxicity against tumor cells. We report here for the first time the cloning of RC-RNase cDNA from liver rather than from oocytes where RC-RNase is stored. An internal fragment of cDNA was obtained by reverse transcription-PCR using deduced oligonucleotides as primers. Full-length cDNA was obtained by 5-and 3-RACE technique. The cDNA clone, named rcr gene, contained a 5-untranslated region, a putative signal peptide (22 amino acids), a mature protein (111 amino acids), a 3-untranslated region, and a polyadenylation site. The cDNA which encoded the mature protein was fused upstream with a modified pelB signal peptide DNA and inserted into pET11d for expression in Escherichia coli strain BL21(DE3). The secretory RC-RNase in the culture medium was enzymatically active and was purified to homogeneity. The recombinant RC-RNase had the same amino acid sequence, specific activity, substrate specificity, antigenicity, and cytotoxicity as that of native RC-RNase from frog oocytes. Amino acid residues His-10, Lys-35, and His-103 are involved in RC-RNase catalytic activity. Ribonucleolytic activity was involved in and may be essential for RC-RNase cytotoxicity. DNA sequence analysis showed that RC-RNase had approximately 45% identity to that of RNase superfamily genes. This indicates that RC-RNase is a distinct ribonuclease gene in the RNase superfamily.

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Section: Amino Acid Sequence and Dna Sequence Homologies In Rnase Supmentioning

confidence: 97%

The Rana catesbeiana rcr Gene Encoding a Cytotoxic Ribonuclease

Huang¹,

Wang²,

Leu³

et al. 1998

Journal of Biological Chemistry

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“…Two groups working independently came to the conclusion that ribonuclease activity was essential to the neurotoxicity of EDN (30,31), but given the unlikelihood of this representing a physiologic phenomenon, the conclusions from this with respect to eosinophil function remain unclear. ECP had been characterized as a generalized cytotoxin, with activity against parasites, bacteria, and mammalian cells (32,33) via what was initially characterized a membrane-disruptive lytic mechanism (34).…”

Section: Ribonuclease Activity and Cytotoxicitymentioning

confidence: 99%

Eosinophils, ribonucleases and host defense: Solving the puzzle

Rosenberg

Domachowske

1999

Immunol Res

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The eosinophil ribonucleases eosinophil-derived neurotoxin (EDN/ RNase 2) and eosinophil cationic protein (ECP/RNase 3) are among the major secretory effector proteins of human eosinophilic leukocytes, cells whose role in host defense remains controversial and poorly understood. We have recently described the unusual manner in which this ribonuclease lineage has evolved, with extraordinary diversification observed in primate as well as in rodent EDNs and ECPs. The results of our evolutionary studies suggest that the EDN/ ECP ribonucleases are in the process of being tailored for a specific, ribonuclease-related goal. With this in mind, we have begun to look carefully at some of the intriguing associations that link eosinophils and their ribonucleases to disease caused by the single-stranded RNA viral pathogen, respiratory syncytial virus (RSV). Recent work in our laboratory has demonstrated that eosinophils can mediate a direct, ribonuclease-dependent reduction in infectivity of RSV in vitro, and that EDN can function alone as an independent antiviral agent. The results of this work have led us to consider the possibility that the EDN/ECP ribonucleases represent a heretofore unrecognized element of innate and specific antiviral host defense.

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“…The current resurgence of interest in RNases is the result of the discovery of RISBASES (RNases with Special Biological Actions), which have been identified to influence tumor cell growth, neurological development, and biological differentiation (2). An important biological function of mammalian RNases may be host defense, as has been observed in the case of the two eosinophil RNases, eosinophil cationic protein and eosinophil-derived neurotoxin, which exhibit antiviral, antibacterial, antiparasitic, and neurotoxic activities (3)(4)(5)(6)(7). Also, frog RNase onconase and bovine seminal ribonuclease (BSRNase) 1 exhibit antitumor activity (8 -11).…”

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confidence: 99%

Interaction of Human Pancreatic Ribonuclease with Human Ribonuclease Inhibitor

Gaur¹,

Swaminathan²,

Batra

2001

Journal of Biological Chemistry

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Mammalian ribonucleases interact very strongly with the intracellular ribonuclease inhibitor (RI). Eukaryotic cells exposed to mammalian ribonucleases are protected from their cytotoxic action by the intracellular inhibition of ribonucleases by RI. Human pancreatic ribonuclease (HPR) is structurally and functionally very similar to bovine RNase A and interacts with human RI with a high affinity. In the current study, we have investigated the involvement of Lys-7, Gln-11, Asn-71, Asn-88, Gly-89, Ser-90, and Glu-111 in HPR in its interaction with human ribonuclease inhibitor. These contact residues were mutated either individually or in combination to generate mutants K7A, Q11A, N71A, E111A, N88R, G89R, S90R, K7A/E111A, Q11A/E111A, N71A/E111A, K7A/ N71A/E111A, Q11A/N71A/E111A, and K7A/Q11A/N71A/ E111A. Out of these, eight mutants, K7A, Q11A, N71A, S90R, E111A, Q11A/E111A, N71A/E111A, and K7A/N71A/ E111A, showed an ability to evade RI more than the wild type HPR, with the triple mutant K7A/N71A/E111A having the maximum RI resistance. As a result, these variants exhibited higher cytotoxic activity than wild type HPR. The mutation of Gly-89 in HPR produced no change in the sensitivity of HPR for RI, whereas it has been reported that mutating the equivalent residue Gly-88 in RNase A yielded a variant with increased RI resistance and cytotoxicity. Hence, despite its considerable homology with RNase A, HPR shows differences in its interaction with RI. We demonstrate that interaction between human pancreatic ribonuclease and RI can be disrupted by mutating residues that are involved in HPR-RI binding. The inhibitor-resistant cytotoxic HPR mutants should be useful in developing therapeutic molecules.

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Toxicity of an antitumor ribonuclease to Purkinje neurons

Cited by 63 publications

References 35 publications

The Rana catesbeiana rcr Gene Encoding a Cytotoxic Ribonuclease

The Rana catesbeiana rcr Gene Encoding a Cytotoxic Ribonuclease

Eosinophils, ribonucleases and host defense: Solving the puzzle

Interaction of Human Pancreatic Ribonuclease with Human Ribonuclease Inhibitor

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