KFERQ sequence in ribonuclease A-mediated cytotoxicity.

Abstract

Onconase(ONC) is an amphibian ribonuclease that is in clinical trials as a cancer chemotherapeutic agent. ONC is a homolog of ribonuclease A (RNase A). RNase A can be made toxic to cancer cells by replacing Gly(88) with an arginine residue, thereby enabling the enzyme to evade the endogenous cytosolic ribonuclease inhibitor protein (RI). Unlike ONC, RNase A contains a KFERQ sequence (residues 7-11), which signals for lysosomal degradation. Here, substitution of Arg(10) of the KFERQ sequence has no effect on either the cytotoxicity of G88R RNase A or its affinity for RI. In contrast, K7A/G88R RNase A is nearly 10-fold more cytotoxic than G88R RNase A and has more than 10-fold less affinity for RI. Up-regulation of the KFERQ-mediated lysosomal degradation pathway has no effect on the cytotoxicity of these ribonucleases. Thus, KFERQ-mediated degradation does not limit the cytotoxicity of RNase A variants. Moreover, only two amino acid substitutions (K7A and G88R) are shown to endow RNase A with cytotoxic activity that is nearly equal to that of ONC.

• Authors: Marcia C Haigis, Erin L Kurten, Richele L Abel, Ronald T Raines
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 13 Pg. 11576-81 (Mar 29 2002) ISSN: 0021-9258 [Print] United States
• PMID: 11801605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Ribonuclease, Pancreatic

Topics

• Amino Acid Sequence
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Division (drug effects)
• Cell Survival (drug effects)
• Humans
• K562 Cells
• Models, Molecular
• Molecular Sequence Data
• Protein Conformation
• Ribonuclease, Pancreatic (chemistry, pharmacology)