Indirubin-3'-monoxime, a derivative of a Chinese anti-leukemia medicine, inhibits Notch1 signaling.
Notch proteins perform a critical function in cell-fate decisions and in differentiation. In this study, we determined that indirubin-3'-monoxime reduced Notch1 signaling to a remarkable extent. Indirubin-3'-monoxime has been shown to inhibit both constitutive active mutants of Notch1 and Notch1-IC-mediated transactivation activity. However, in such cases, neither the Notch cleavage pattern nor the protein stability of Notch1-IC was determined to have been significantly altered. Indirubin-3'-monoxime suppresses Notch1 transcriptional activity via the dissociation of the Notch1-IC-RBP-Jk complex. Notably, the transcriptional activity of Notch1-IC was not suppressed significantly in the GSK-3beta null cells by indirubin-3'-monoxime as compared to what was observed with GSK-3beta wild-type cells. In the previous study, we synthesized a series of indirubin derivatives. Interestingly, some of these indirubin derivatives were characterized as potent inhibitors of Notch1 signaling. Taken together, the results of this study indicate that indirubin-3'-monoxime downregulated Notch1 signaling in a GSK-3beta-dependent and proteosomal degradation-independent manner.
Lee
Mi-Jee
MJ
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Yongbong-dong, Gwangju, Republic of Korea.
Kim
Mi-Yeon
MY
Mo
Jung-Soon
JS
Ann
Eun-Jung
EJ
Seo
Mi-Sun
MS
Hong
Ji-Ae
JA
Kim
Yong-Chul
YC
Park
Hee-Sae
HS
D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D007211:Indoles; D010091:Oximes; D051880:Receptors, Notch; C474021:indirubin-3'-monoxime; D038362:Glycogen Synthase Kinase 3