Notch1 oncoprotein antagonizes TGF-beta/Smad-mediated cell growth suppression via sequestration of coactivator p300.
The Notch proteins constitute a family of transmembrane receptors that play a pivotal role in cellular differentiation, proliferation and apoptosis. Although it has been recognized that excess Notch signaling is potentially tumorigenic, little is known about precise mechanisms through which dysregulated Notch signaling induces neoplastic transformation. Here we demonstrate that Notch signaling has a transcriptional cross-talk with transforming growth factor-beta (TGF-beta) signaling, which is well characterized by its antiproliferative effects. TGF-beta-mediated transcriptional responses are suppressed by constitutively active Notch1, and this inhibitory effect is canceled by introduction of transcriptional coactivator p300. We further show that this blockade of TGF-beta signaling is executed by the sequestration of p300 from Smad3. Moreover, in a human cervical carcinoma cell line, CaSki, in which Notch1 is spontaneously activated, suppression of Notch1 expression with small interfering RNA significantly restores the responsiveness to TGF-beta. Taken together, we propose that Notch oncoproteins promote cell growth and cancer development partly by suppressing the growth inhibitory effects of TGF-beta through sequestrating p300 from Smad3.
Masuda
Shigeo
S
Department of Hematology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Kumano
Keiki
K
Shimizu
Kiyoshi
K
Imai
Yoichi
Y
Kurokawa
Mineo
M
Ogawa
Seishi
S
Miyagishi
Makoto
M
Taira
Kazunari
K
Hirai
Hisamaru
H
Chiba
Shigeru
S
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050881:E1A-Associated p300 Protein; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse