The farnesyl protein transferase inhibitor BZA-5B blocks farnesylation of nuclear lamins and p21ras but does not affect their function or localization.
BZA-5B is a peptidomimetic inhibitor of protein farnesylation in mammalian cells. We have examined the specificity of this compound toward inhibition of farnesylation of p21ras and the nuclear lamin proteins, prelamin A and lamin B. We have also used the Raney nickel cleavage technique in conjunction with radio-gas liquid chromatography to assess the ability of this compound to block total protein farnesylation. These studies show that BZA-5B blocks farnesylation of the lamin proteins with an IC50 comparable to that seen for p21ras. At a concentration in excess of 25 microM, BZA-5B inhibits all protein farnesylation in CHO-K1 cells below the limits of detection. Furthermore, we found that after a 2-day exposure to high concentrations of BZA-5B, CHO-K1 cell lines exhibit no loss in sensitivity to inhibition of prenylation by this compound. Yet, despite the potent and general inhibition of protein farnesylation, BZA-5B does not interfere with a variety of cellular functions expected to be farnesylation dependent, including cell growth and viability, assembly of the nuclear lamina, membrane association of p21ras, and p21ras-dependent differentiation of PC-12 cells in response to treatment with nerve growth factor. The maintenance of farnesylation-dependent events in the presence of BZA-5B stands in marked contrast to the inhibition of the oncogenic ras-mediated transformed phenotype that has been observed with this compound and other farnesyl protein transferase inhibitors. This specificity for inhibition of ras transformation by BZA-5B is quite encouraging to its eventual development as an antimalignancy pharmaceutical.[1]References
- The farnesyl protein transferase inhibitor BZA-5B blocks farnesylation of nuclear lamins and p21ras but does not affect their function or localization. Dalton, M.B., Fantle, K.S., Bechtold, H.A., DeMaio, L., Evans, R.M., Krystosek, A., Sinensky, M. Cancer Res. (1995) [Pubmed]
Annotations and hyperlinks in this abstract are from individual authors of WikiGenes or automatically generated by the WikiGenes Data Mining Engine. The abstract is from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.About WikiGenesOpen Access LicencePrivacy PolicyTerms of Useapsburg
