Using C. Elegans as Model Organism to Study the Mode of Action of a Natural Toxin, Psymberin

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Title: Using C. Elegans as Model Organism to Study the Mode of Action of a Natural Toxin, Psymberin
Author: Wu, Cheng-Yang
Abstract: Psymberin is an extremely potent cytotoxin isolated from the marine sponges Psammocinia and Ircinia ramose . Several cancer cell lines are sensitive to psymberin , including breast , melanoma and colon cancer cell lines . Psymberin is the only member of the pederin natural product family that contains a dihydroisocoumarin side chain . The cytotoxicities of psymberin in various human tumor cell lines are between sub -nanomolar to nanomolar IC50 . Like pederin , the first member of this natural product family , psymberin and mycalamide A inhibit translation in vivo and in vitro . This inhibition by psymberin is 40 to 100 fold more potent than cycloheximide , which inhibits >90 % translation at 100 micromolar in vivo . In a SAR study , both the cytotoxicity of psymberin and psymberin -induced translation inhibition were attenuated by substituting the psymberin side chain with the pederin side chain . However , the attenuation of cytotoxicity was relatively greater than of translation . The stereo configuration and both side chains of psymberin are required for both inhibition of translation and cytotoxicity . The result of the SAR study suggests that additional bioactivity is contained in psymberin . Psymberin is at best a poor substrate for small molecule pumps in the cell . Two separate forward genetics screens in C . elegans isolated seven independent psymberin -resistant mutants . In each the mutation was a C361T point mutation in the rpl -41 gene that changes Pro65 to Leu65 in the protein coding sequence . The psymberin -resistant mutant strain DA2312 is resistant to psymberin only . This mutation did not appear to cause weaker binding of psymberin to the ribosome , but must allow translation to continue with the toxin bound . There are additional modes of actions of psymberin compared to mycalamide A . The endogenous protein level of LC3 , an autophagy marker , is decreased faster with psymberin treatment than mycalamide A . In HT -29 cells , psymberin is capable of synergizing TNFa -induced necrotic cell death more efficiently than mycalamide A . The results from SAR study and from study of the psymberin -specific mutation in C . elegans suggest that psymberin may induce fast cell death through multiple pathways , including translation inhibition , apoptosis and necrosis . The structural uniqueness of psymberin has functional consequences suggesting that the mode of action of psymberin on the ribosome is different from other members of the pederin family .
URI: http : / /hdl .handle .net /2152 .5 /956
Date: 2011-12-15

Citation

Using C. Elegans as Model Organism to Study the Mode of Action of a Natural Toxin, Psymberin. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /956 .

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