Abstract:
:We have recently identified several novel ATP-independent inhibitors that target the extracellular signal-regulated kinase-2 (ERK2) protein and inhibit substrate phosphorylation. To further characterize these compounds, we describe the use of C. elegans as a model organism. C. elegans is recognized as a versatile and cost effective model for use in drug development. These studies take advantage of the well characterized process of vulva development and egg laying, which requires MPK-1, the homolog to human ERK2. It is shown that treatment of C. elegans eggs or larvae prior to vulva formation with a previously identified lead compound (76) caused up to 50% reduction in the number of eggs produced from the adult worm. In contrast, compound 76 had no effect on egg laying in young adult or adult worms with fully formed vulva. The reduction in egg laying by the test compound was not due to effects on C. elegans life span, general toxicity, or non-specific stress. However, compound 76 did show selective inhibition of phosphorylation of LIN-1, a MPK-1 substrate essential for vulva precursor cell formation. Moreover, compound 76 inhibited cell fusion necessary for vulva maturation and reduced the multivulva phenotype in LET-60 (Ras) mutant worms that have constitutive activation of MPK-1. These findings support the use of C. elegans as a model organism to evaluate the selectivity and specificity of novel ERK targeted compounds.
journal_name
J Cell Commun Signaljournal_title
Journal of cell communication and signalingauthors
Chen F,Mackerell AD Jr,Luo Y,Shapiro Pdoi
10.1007/s12079-008-0034-2subject
Has Abstractpub_date
2008-12-01 00:00:00pages
81-92issue
3-4eissn
1873-9601issn
1873-961Xjournal_volume
2pub_type
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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journal_title:Journal of cell communication and signaling
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