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

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276 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 languageEnglish (US)
Pages (from-to)1101-1113
Number of pages13
JournalNeuron
Volume21
Issue number5
DOIs
StatePublished - Nov 1998

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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