Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop.
Transcription of messenger RNAs (mRNAs) for Notch signaling molecules oscillates with 2-hour cycles, and this oscillation is important for coordinated somite segmentation. However, the molecular mechanism of such oscillation remains to be determined. Here, we show that serum treatment of cultured cells induces cyclic expression of both mRNA and protein of the Notch effector Hes1, a basic helix-loop-helix (bHLH) factor, with 2-hour periodicity. Cycling is cell-autonomous and depends on negative autoregulation of hes1 transcription and ubiquitin-proteasome-mediated degradation of Hes1 protein. Because Hes1 oscillation can be seen in many cell types, this clock may regulate timing in many biological systems.
Hirata
Hiromi
H
Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Yoshiura
Shigeki
S
Ohtsuka
Toshiyuki
T
Bessho
Yasumasa
Y
Harada
Takahiro
T
Yoshikawa
Kenichi
K
Kageyama
Ryoichiro
R
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001683:Biological Clocks; D001769:Blood; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D006207:Half-Life; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D016716:PC12 Cells; D010507:Periodicity; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
D000111:Acetylcysteine; D051792:Basic Helix-Loop-Helix Proteins; D003513:Cycloheximide; D003546:Cysteine Endopeptidases; D016695:Glycosyltransferases; D018398:Homeodomain Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D046988:Proteasome Endopeptidase Complex; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D000072056:Transcription Factor HES-1; D025801:Ubiquitin; C489734:Hes1 protein, mouse; C489735:Hes1 protein, rat; C067713:lactacystin; C498392:Lfng protein, mouse; C498391:Lfng protein, rat; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde