A beta-lactone related to lactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibits cell cycle progression in an osteosarcoma cell line.
- 12 April 1994
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 91 (8) , 3358-3362
- https://doi.org/10.1073/pnas.91.8.3358
Abstract
Lactacystin, a microbial natural product, induces neurite outgrowth in Neuro 2A mouse neuroblastoma cells and inhibits progression of synchronized Neuro 2A cells and MG-63 human osteosarcoma cells beyond the G1 phase of the cell cycle. A related beta-lactone, clasto-lactacystin beta-lactone, formally the product of elimination of N-acetylcysteine from lactacystin, is also active, whereas the corresponding clastolactacystin dihydroxy acid is completely inactive. Structural analogs of lactacystin altered only in the N-acetylcysteine moiety are active, while structural or stereochemical modifications of the gamma-lactam ring or the hydroxyisobutyl group lead to partial or complete loss of activity. The inactive compounds do not antagonize the effects of lactacystin in either neurite outgrowth or cell cycle progression assays. The response to lactacystin involves induction of a predominantly bipolar morphology that is maximal 16-32 h after treatment and is distinct from the response to several other treatments that result in morphological differentiation. Neurite outgrowth in response to lactacystin appears to be dependent upon microtubule assembly, actin polymerization, and de novo protein synthesis. The observed structure-activity relationships suggest that lactacystin and its related beta-lactone may act via acylation of one or more relevant target molecule(s) in the cell.Keywords
This publication has 21 references indexed in Scilit:
- Opposing influences of protein kinase activities on neurite outgrowth in human neuroblastoma cells: Initiation by kinase A and restriction by kinase CJournal of Neuroscience Research, 1992
- Quantitative analysis of CD5 antigen modulation by 12-O-tetradecanoylphorbol-13-acetate in T-lymphoblastic leukemia cells: Individual response patterns and their relationships with both maturation and protein kinase C contentCellular Immunology, 1990
- Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A synthase by antibiotic 1233A and other β-lactonesBiochemical and Biophysical Research Communications, 1990
- Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase CBiochemical and Biophysical Research Communications, 1989
- Mode of action of tetrahydrolipstatin: a derivative of the naturally occurring lipase inhibitor lipstatinBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1988
- Cell-derived proteases and protease inhibitors as regulators of neurite outgrowthTrends in Neurosciences, 1988
- Lysosphingolipids Inhibit Protein Kinase C: Implications for the SphingolipidosesScience, 1987
- A glia-derived neurite promoting factor with protease inhibitory activity belongs to the protease nexinsCell, 1986
- Electronic-transport behavior in single-crystallinePhysical Review B, 1986
- Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide-dependent protein kinase and protein kinase CBiochemistry, 1984