Molecular Analysis of Mammalian Timeless

Zylka, Mark J.; Shearman, Lauren P.; Levine, Joel D.; Jin, Xiaowei; Weaver, David R.; Reppert, Steven M.

doi:10.1016/s0896-6273(00)80628-5

Cited by 171 publications

(135 citation statements)

References 41 publications

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“…Furthermore, in the retina, mTim mRNA was found to be expressed with a circadian rhythm, and a particularly robust cycle was observed in the presence of light/dark cycles. This rhythmic expression has not previously been reported, and mTim mRNA expression was not examined in the presence of environmental cycles in either of the earlier studies (Sangoram et al 1998;Zylka et al 1998).…”

Section: Discussionmentioning

confidence: 75%

“…Yeast two-hybrid assays by Zylka et al (1998) revealed no mPER-mTIM interactions, while Sangoram et al (1998) showed that hTIM interacts with the Drosophila PERIOD (dPER) in vitro and hTIM and dPER interact and translocate in the nucleus in Drosophila S2 cells. In the present study, mTIM and mPER1 were found to interact, and were recovered from the nuclei of mammalian COS7 cells.…”

Section: Discussionmentioning

confidence: 99%

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A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1

et al. 1999

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Background: It is now becoming clear that the circadian rhythm of behaviours and hormones arises from a rhythm at the level of gene expression, and that mammals and Drosophila essentially use homologous genes as molecular gears in the control of circadian oscillation. In Drosophila, the period and timeless genes form a functional unit of the clock and its autoregulatory feedback loop for circadian rhythm. However, in mammals, the counterpart of timeless has not been found.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1

et al. 1999

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“…One of the breakthroughs in the field of circadian biology in the past 10 years has been the recognition that intrinsic oscillators are present in most peripheral tissues (1)(2)(3). It is conceivable that many millions of years ago, most cells were sensitive to light-dark cycles, and furthermore, we know that most eukaryotic cells undergo division in culture with a periodicity of 1 day.…”

Section: Resultsmentioning

confidence: 99%

“…In humans, the central pacemaker of the circadian clock is located in the suprachiasmatic nucleus of the anterior hypothalamus. One of the discoveries that has deeply affected the field of circadian biology is the discovery that molecular clockwork similar to that present in suprachiasmatic nucleus neurons exists in all peripheral tissues studied (1)(2)(3). Circadian oscillations even occur in established cell lines, such as cultured fibroblasts, in which the endogenous clock system needs a simple serum shock to be synchronized (4).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies

et al. 2009

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Disruption of circadian rhythms, daily oscillations in biological processes that are regulated by an endogenous clock, has been linked to tumorigenesis. Normal and malignant tissues often show asynchronies in cell proliferation and metabolic rhythms. Cancer chronotherapy takes biological time into account to improve the therapy. However, alterations of the circadian clock machinery genes have rarely been reported in human cancer. Herein, we show that the BMAL1 gene, a core component of the circadian clock, is transcriptionally silenced by promoter CpG island hypermethylation in hematologic malignancies, such as diffuse large B-cell lymphoma and acute lymphocytic and myeloid leukemias. We also describe how BMAL1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas BMAL1 depletion by RNA interference in unmethylated cells enhances tumor growth. We also show that BMAL1 epigenetic inactivation impairs the characteristic circadian clock expression pattern of genes such as C-MYC, catalase, and p300 in association with a loss of BMAL1 occupancy in their respective promoters. Furthermore, the DNA hypermethylation-associated loss of BMAL1 also prevents the recruitment of its natural partner, the CLOCK protein, to their common targets, further enhancing the perturbed circadian rhythm of the malignant cells. These findings suggest that BMAL1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting the cellular circadian clock. [Cancer Res 2009;69(21):8447-54]

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“…Mammals do not have a true ortholog of Drosophila TIM1 but rather have an ortholog of Drosophila Timeout (dTIM2), a gene with no known function in the fly's clock. Mammalian TIM is expressed in the suprachiasmatic nucleus (SCN), the site of the mammalian pacemaker, but there is an ongoing debate concerning its role, if any, in central rhythm generation (Zylka et al 1998;Takumi et al 1999;Field et al 2000;Gotter at al. 2000;Barnes et al 2003).…”

mentioning

confidence: 99%

Molecular and phylogenetic analyses reveal mammalian-like clockwork in the honey bee (Apis mellifera) and shed new light on the molecular evolution of the circadian clock

et al. 2006

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The circadian clock of the honey bee is implicated in ecologically relevant complex behaviors. These include time sensing, time-compensated sun-compass navigation, and social behaviors such as coordination of activity, dance language communication, and division of labor. The molecular underpinnings of the bee circadian clock are largely unknown. We show that clock gene structure and expression pattern in the honey bee are more similar to the mouse than to Drosophila. The honey bee genome does not encode an ortholog of Drosophila Timeless (Tim1), has only the mammalian type Cryptochrome (Cry-m), and has a single ortholog for each of the other canonical "clock genes." In foragers that typically have strong circadian rhythms, brain mRNA levels of amCry, but not amTim as in Drosophila, consistently oscillate with strong amplitude and a phase similar to amPeriod (amPer) under both light-dark and constant darkness illumination regimes. In contrast to Drosophila, the honey bee amCYC protein contains a transactivation domain and its brain transcript levels oscillate at virtually an anti-phase to amPer, as it does in the mouse. Phylogenetic analyses indicate that the basal insect lineage had both the mammalian and Drosophila types of Cry and Tim. Our results suggest that during evolution, Drosophila diverged from the ancestral insect clock and specialized in using a set of clock gene orthologs that was lost by both mammals and bees, which in turn converged and specialized in the other set. These findings illustrate a previously unappreciated diversity of insect clockwork and raise critical questions concerning the evolution and functional significance of species-specific variation in molecular clockwork.

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Molecular Analysis of Mammalian Timeless

Cited by 171 publications

References 41 publications

A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1

A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1

Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies

Molecular and phylogenetic analyses reveal mammalian-like clockwork in the honey bee (Apis mellifera) and shed new light on the molecular evolution of the circadian clock

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