Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription.
We report the cloning and mapping of mouse (mTim) and human (hTIM) orthologs of the Drosophila timeless (dtim) gene. The mammalian Tim genes are widely expressed in a variety of tissues; however, unlike Drosophila, mTim mRNA levels do not oscillate in the suprachiasmatic nucleus (SCN) or retina. Importantly, hTIM interacts with the Drosophila PERIOD (dPER) protein as well as the mouse PER1 and PER2 proteins in vitro. In Drosophila (S2) cells, hTIM and dPER interact and translocate into the nucleus. Finally, hTIM and mPER1 specifically inhibit CLOCK-BMAL1-induced transactivation of the mPer1 promoter. Taken together, these results demonstrate that mTim and hTIM are mammalian orthologs of timeless and provide a framework for a basic circadian autoregulatory loop in mammals.
Sangoram
A M
AM
Department of Neurobiology and Physiology and National Science Foundation, Center for Biological Timing, The Rockefeller University, New York, New York 10021, USA.
Saez
L
L
Antoch
M P
MP
Gekakis
N
N
Staknis
D
D
Whiteley
A
A
Fruechte
E M
EM
Vitaterna
M H
MH
Shimomura
K
K
King
D P
DP
Young
M W
MW
Weitz
C J
CJ
Takahashi
J S
JS
D056930:ARNTL Transcription Factors; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001683:Biological Clocks / Q000235:genetics; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D003001:Cloning, Molecular; D004330:Drosophila; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D056950:Period Circadian Proteins; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C539022:PER1 protein, human; C539023:Per1 protein, mouse; C509769:TIMELESS protein, human; C509770:Timeless protein, mouse; C096445:tim protein, Drosophila; C538943:CLOCK protein, human; C538944:Clock protein, mouse