Jun/Fos, a crucial factor in transmitting the tumor-promoting signal from the extracellular environment to the nuclear transcription machinery, has a dimerization interface possessing several coiled structural properties. Jun and Fos can interact with the DNA regulatory region, AP-1 (Activator Prote...
Jun/Fos, a crucial factor in transmitting the tumor-promoting signal from the extracellular environment to the nuclear transcription machinery, has a dimerization interface possessing several coiled structural properties. Jun and Fos can interact with the DNA regulatory region, AP-1 (Activator Protein-1), which is composed of 5'-TGAC/GTCA-3'.$^1$ Curcumin is a well-known anticancer and anti-inflammatory compound.$^{2,3}$ It also acts as an inhibitor of the Jun-Fos function. c-Fos and c-Jun with a bZIP region are overexpressed in BL21 E. coli and purified with an $Ni^{2+}$ affinity column. The inhibitors of Fos-Jun-AP-1 complex formation were searched through the EMSA (electrophoresis mobility shift assay) experiment, and new curcuminoids were synthesized and investigated as to their inhibitory effect on the same system. Two curcuminoids showed a stronger inhibitory effect than curcumin. This inhibitory activity was quantified with EMSA. 1,7-bis(4-methyl)-1,6-heptadiene-3,5-dione (BJC003) and 1,7-bis(4-hydroxy-5-methoxy-3-nitrophenyl)-1,6-heptadiene-3,5-dione (BJC005) showed remarkably high inhibitory activities. $IC_{50}$ of 1,7-bis(4-methyl)-1,6-heptadiene-3,5-dione (BJC003) and 1,7-bis(4-hydroxy-5-methoxy-3-nitrophenyl)-1,6-heptadiene-3,5-dione (BJC005) are 8.98 ${\mu}M$ and 5.40 ${\mu}M$, respectively. However, 1,7-bis(4-methyl-3-nitrophenyl)-1,6-heptadiene-3,5-dione (BJC004) did not show inhibitory activity.
Jun/Fos, a crucial factor in transmitting the tumor-promoting signal from the extracellular environment to the nuclear transcription machinery, has a dimerization interface possessing several coiled structural properties. Jun and Fos can interact with the DNA regulatory region, AP-1 (Activator Protein-1), which is composed of 5'-TGAC/GTCA-3'.$^1$ Curcumin is a well-known anticancer and anti-inflammatory compound.$^{2,3}$ It also acts as an inhibitor of the Jun-Fos function. c-Fos and c-Jun with a bZIP region are overexpressed in BL21 E. coli and purified with an $Ni^{2+}$ affinity column. The inhibitors of Fos-Jun-AP-1 complex formation were searched through the EMSA (electrophoresis mobility shift assay) experiment, and new curcuminoids were synthesized and investigated as to their inhibitory effect on the same system. Two curcuminoids showed a stronger inhibitory effect than curcumin. This inhibitory activity was quantified with EMSA. 1,7-bis(4-methyl)-1,6-heptadiene-3,5-dione (BJC003) and 1,7-bis(4-hydroxy-5-methoxy-3-nitrophenyl)-1,6-heptadiene-3,5-dione (BJC005) showed remarkably high inhibitory activities. $IC_{50}$ of 1,7-bis(4-methyl)-1,6-heptadiene-3,5-dione (BJC003) and 1,7-bis(4-hydroxy-5-methoxy-3-nitrophenyl)-1,6-heptadiene-3,5-dione (BJC005) are 8.98 ${\mu}M$ and 5.40 ${\mu}M$, respectively. However, 1,7-bis(4-methyl-3-nitrophenyl)-1,6-heptadiene-3,5-dione (BJC004) did not show inhibitory activity.
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제안 방법
6 AP-1 has two oncogene products with its own components, namely, Jun and Fos. In this report, in order to search for a more potent Fos/Jun inhibitor, we synthesized a series of symmetrical curcumin analogs by Pabons method2 and tested their inhibitory activity by performing gel-retardation assay.
대상 데이터
The positions of unbound DNA and purified Fos-Jun-DNA complex are indicated. 32P-radiolabeled AP-1 DNA was used. All inhibitors were dissolved in DMSO and used in 0.
이론/모형
11,12 They were >95% homogeneous as determined by SDS-PAGE. The concentrations ofproteins were determined by Bradford assay. The concentrations of purified Jun and Fos were 129 //L/mL and 36.
후속연구
In summary, our results clearly demonstrated that synthesized curcumin analogs, such as BJC003 and BJC004 show more potent inhibitory activities against Fos-Jun-DNA complex formation than curcumin and momordin. Further study is required to determine the precise molecular mechanism of inhibition by curcuminoids.
참고문헌 (13)
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Angel, P. E.; Herrlich, P. A. The Fos and Jun Families ofTranscription Factors; CRC press: U.S.A., 1994; pp 169-286.
Smith, P. K.; Krohn, R. I.; Hermanson, G. T.; Mallia, A. K.;Gartner, F. H.; Provenzano, M. D.; Fujimoto, E. K.; Goeke, N. M.;Olson, B. J.; Klenk, D. C. Anal. Biochem. 1985, 150, 76-85.
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