Mammalian circadian autoregulatory loop: A timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription

Ashvin M. Sangoram; Lino Saez; Marina P. Antoch; Nicholas Gekakis; David Staknis; Andrew Whiteley; Ethan M. Fruechte; Martha Hotz Vitaterna; Kazuhiro Shimomura; David P. King; Michael W. Young; Charles J. Weitz; Joseph S. Takahashi

doi:10.1016/S0896-6273(00)80627-3

Mammalian circadian autoregulatory loop: A timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription

Ashvin M. Sangoram, Lino Saez, Marina P. Antoch, Nicholas Gekakis, David Staknis, Andrew Whiteley, Ethan M. Fruechte, Martha Hotz Vitaterna, Kazuhiro Shimomura, David P. King, Michael W. Young, Charles J. Weitz, Joseph S. Takahashi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

316 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1101-1113
Number of pages	13
Journal	Neuron
Volume	21
Issue number	5
DOIs	https://doi.org/10.1016/S0896-6273(00)80627-3
State	Published - Nov 1998

Funding

We thank D. Spicer and A. Lassar for generously providing MyoD, E12, and Id expression plasmids and mck-luciferase reporter gene construct; M. B. Kelz and members of the Takahashi laboratory for useful discussions; D. J. Bernard for assistance with in situ hybridization; T. D. L. Steeves, E.-J. Song, and J. Kushla for technical assistance; and A.-M. Chang for help with the manuscript. Research was supported by the NSF Center for Biological Timing (J. S. T. and M. W. Y.), an Unrestricted Research Grant in Neuroscience from Bristol-Myers Squibb (J. S. T.), an NSF grant and McKnight Scholars Award (C. J. W.), and NIH GM54339 (M. W. Y.). A. W. is a Research Technologist, K. S. is a Research Associate, and J. S. T. is an Investigator in the Howard Hughes Medical Institute.

ASJC Scopus subject areas

General Neuroscience

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10.1016/S0896-6273(00)80627-3

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Sangoram, A. M., Saez, L., Antoch, M. P., Gekakis, N., Staknis, D., Whiteley, A., Fruechte, E. M., Vitaterna, M. H., Shimomura, K., King, D. P., Young, M. W., Weitz, C. J., & Takahashi, J. S. (1998). Mammalian circadian autoregulatory loop: A timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron, 21(5), 1101-1113. https://doi.org/10.1016/S0896-6273(00)80627-3

@article{e568416a1e96463e98f630db8925c531,

title = "Mammalian circadian autoregulatory loop: A timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription",

abstract = "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.",

author = "Sangoram, {Ashvin M.} and Lino Saez and Antoch, {Marina P.} and Nicholas Gekakis and David Staknis and Andrew Whiteley and Fruechte, {Ethan M.} and Vitaterna, {Martha Hotz} and Kazuhiro Shimomura and King, {David P.} and Young, {Michael W.} and Weitz, {Charles J.} and Takahashi, {Joseph S.}",

note = "Funding Information: We thank D. Spicer and A. Lassar for generously providing MyoD, E12, and Id expression plasmids and mck-luciferase reporter gene construct; M. B. Kelz and members of the Takahashi laboratory for useful discussions; D. J. Bernard for assistance with in situ hybridization; T. D. L. Steeves, E.-J. Song, and J. Kushla for technical assistance; and A.-M. Chang for help with the manuscript. Research was supported by the NSF Center for Biological Timing (J. S. T. and M. W. Y.), an Unrestricted Research Grant in Neuroscience from Bristol-Myers Squibb (J. S. T.), an NSF grant and McKnight Scholars Award (C. J. W.), and NIH GM54339 (M. W. Y.). A. W. is a Research Technologist, K. S. is a Research Associate, and J. S. T. is an Investigator in the Howard Hughes Medical Institute. ",

year = "1998",

month = nov,

doi = "10.1016/S0896-6273(00)80627-3",

language = "English (US)",

volume = "21",

pages = "1101--1113",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

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Sangoram, AM, Saez, L, Antoch, MP, Gekakis, N, Staknis, D, Whiteley, A, Fruechte, EM, Vitaterna, MH, Shimomura, K, King, DP, Young, MW, Weitz, CJ & Takahashi, JS 1998, 'Mammalian circadian autoregulatory loop: A timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription', Neuron, vol. 21, no. 5, pp. 1101-1113. https://doi.org/10.1016/S0896-6273(00)80627-3

TY - JOUR

T1 - Mammalian circadian autoregulatory loop

T2 - A timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription

AU - Sangoram, Ashvin M.

AU - Saez, Lino

AU - Antoch, Marina P.

AU - Gekakis, Nicholas

AU - Staknis, David

AU - Whiteley, Andrew

AU - Fruechte, Ethan M.

AU - Vitaterna, Martha Hotz

AU - Shimomura, Kazuhiro

AU - King, David P.

AU - Young, Michael W.

AU - Weitz, Charles J.

AU - Takahashi, Joseph S.

N1 - Funding Information: We thank D. Spicer and A. Lassar for generously providing MyoD, E12, and Id expression plasmids and mck-luciferase reporter gene construct; M. B. Kelz and members of the Takahashi laboratory for useful discussions; D. J. Bernard for assistance with in situ hybridization; T. D. L. Steeves, E.-J. Song, and J. Kushla for technical assistance; and A.-M. Chang for help with the manuscript. Research was supported by the NSF Center for Biological Timing (J. S. T. and M. W. Y.), an Unrestricted Research Grant in Neuroscience from Bristol-Myers Squibb (J. S. T.), an NSF grant and McKnight Scholars Award (C. J. W.), and NIH GM54339 (M. W. Y.). A. W. is a Research Technologist, K. S. is a Research Associate, and J. S. T. is an Investigator in the Howard Hughes Medical Institute.

PY - 1998/11

Y1 - 1998/11

N2 - 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.

AB - 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.

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AN - SCOPUS:0032214514

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JO - Neuron

JF - Neuron

IS - 5

ER -

Mammalian circadian autoregulatory loop: A timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription

Abstract

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