A time-less function for mouse Timeless

Gotter, Anthony L.; Manganaro, Thomas F.; Weaver, David R.; Kolakowski, Lee F.; Possidente, Bernard; Sathyanarayanan, Sriram; MacLaughlin, David T.; Reppert, Steven M.

doi:10.1038/77653

Cited by 163 publications

(144 citation statements)

References 10 publications

Supporting

Mentioning

140

Contrasting

Unclassified

Order By: Relevance

“…TIMELESS belongs to a protein family that includes a second Drosophila protein, dTIMEOUT, or dTIM2, which is homologous to mouse (mTIM) and Caenorhabditis elegans (ceTIM-1) proteins involved in development (11,12,23). However, apTIM is more closely related to dTIM than to dTIMEOUT (11,12), indicating that it is an ortholog of dTIM, rather than of dTIMEOUT.…”

Section: Resultsmentioning

confidence: 99%

Constructing a Feedback Loop with Circadian Clock Molecules from the Silkmoth, Antheraea pernyi

Chang

McWatters

Williams

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Circadian clocks are important regulators of behavior and physiology. The circadian clock of Drosophila depends on an autoinhibitory feedback loop involving dCLOCK, CYCLE (also called dBMAL, for Drosophila brain and muscle ARNT-like protein), dPERIOD, and dTIMELESS. Recent studies suggest that the clock mechanism in other insect species may differ strikingly from that of Drosophila. We cloned Clock, Bmal, and Timeless homologs (apClock, apBmal, and apTimeless) from the silkmoth Antheraea pernyi, from which a Period homolog (apPeriod) has already been cloned. In Schneider 2 (S2) cell culture assays, apCLOCK:apBMAL activates transcription through an E-box enhancer element found in the 5 region of the apPeriod gene. Furthermore, apPERIOD can robustly inhibit apCLOCK: apBMAL-mediated transactivation, and apTIMELESS can augment this inhibition. Thus, a complete feedback loop, resembling that found in Drosophila, can be constructed from silkmoth CLOCK, BMAL, PERIOD, and TIMELESS. Our results suggest that the circadian autoinhibitory feedback loop discovered in Drosophila is likely to be widespread among insects. However, whereas the transactivation domain in Drosophila lies in the C terminus of dCLOCK, in A. pernyi, it lies in the C terminus of apBMAL, which is highly conserved with the C termini of BMALs in other insects (except Drosophila) and in vertebrates. Our analysis sheds light on the molecular function and evolution of clock genes in the animal kingdom.

show abstract

Section: Resultsmentioning

confidence: 99%

Constructing a Feedback Loop with Circadian Clock Molecules from the Silkmoth, Antheraea pernyi

Chang

McWatters

Williams

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…In contrast, a single TIM gene has been identified in mammals, which acquired all of these functions as indicated by its role in DNA damage response, replication, and circadian rhythm (5)(6)(7)(8)(9). Consistently, TIM knockout resulted in embryonic lethality in mice (10). In addition, TIM and other clock genes have been linked to human carcinogenesis (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 98%

Protumorigenic role of Timeless in hepatocellular carcinoma

Elgohary

Pellegrino

Neumann

et al. 2014

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. The mammalian timeless (TIM) protein interacts with proteins of the endogenous clock and essentially contributes to the circadian rhythm. In addition, TIM is involved in maintenance of chromosome integrity, growth control and development. Thus, we hypothesized that TIM may exert a potential protumorigenic function in human hepatocarcinogenesis. TIM was overexpressed in a subset of human HCCs both at the mRNA and the protein level. siRNA-mediated knockdown of TIM reduced cell viability due to the induction of apoptosis and G2 arrest. The latter was mediated via CHEK2 phosphorylation. In addition, siRNA-treated cells showed a significantly reduced migratory capacity and reduced expression levels of various proteins. Mechanistically, TIM directly interacts with the eukaryotic elongation factor 1A2 (EEF1A2), which binds to actin filaments to promote tumor cell migration. siRNA-mediated knockdown of TIM reduced EEF1A2 protein levels thereby affecting ribosomal protein biosynthesis. Thus, overexpression of TIM exerts oncogenic function in human HCCs, which is mediated via CHEK2 and EEF1A2. IntroductionMany biological processes show a circadian rhythm, which is controlled by an endogenous clock that synchronizes with day and night phases of the solar day. The periodical rhythm is generated by a molecular oscillator located in the suprachiasmatic nuclei of the hypothalamus, which controls peripheral oscillators in virtually any other cell (1). The circadian clock is organized through a complex network of transcriptiontranslational feedback loops that drive rhythmic expression patterns of core clock components in mammals (2).The Timeless (TIM) protein interacts with clock proteins and is essential for generation of a circadian rhythm in flies (3). In addition, phylogenetic sequence analysis revealed the presence of a paralogue in D. melanogaster (4), which is not involved in the core clock machinery, but is important for the maintenance of chromosome integrity, growth control, and development. In contrast, a single TIM gene has been identified in mammals, which acquired all of these functions as indicated by its role in DNA damage response, replication, and circadian rhythm (5-9). Consistently, TIM knockout resulted in embryonic lethality in mice (10). In addition, TIM and other clock genes have been linked to human carcinogenesis (11)(12)(13)(14). Using integrative molecular profiling we have recently identified that inactivation of Period homolog 3, a component of the clock machinery, occurs in human HCC indicating that dysregulation of this regulatory network may contribute to hepatocarcinogenesis (15).The eukaryotic elongation factor 1-α (EEF1A), a member of the G protein family, represents one of the four subunits that constitute the eukaryotic elongation factor 1 (16). In humans,

show abstract

“…A structurally related paralog in Drosophila, Timeout, has been identified (5). This is an essential gene in mice (6). In C. elegans the Timeless protein, Tim1, may actually be more functionally related to Timeout and has been shown to play an important role in sister chromatid cohesion (4).…”

mentioning

confidence: 99%

Tipin and Timeless form a mutually protective complex required for genotoxic stress resistance and checkpoint function

Chou

Elledge²

2006

Proc. Natl. Acad. Sci. U.S.A.

149

151

View full text Add to dashboard Cite

Tipin is a mammalian protein that interacts with Timeless, which plays a role in DNA damage checkpoint responses. Here, we show that Tipin is a nuclear protein that associates with the replicative helicase and protects cells against genotoxic agents. Tipin is required for efficient cell cycle arrest in response to DNA damage, and depletion of Tipin renders cells sensitive to ionizing radiation as well as replication stress. Loss of Tipin results in spontaneous ␥-H2AX foci, a marker for DNA double-strand breaks. We find that Tipin and Timeless form a complex that maintains the level of both proteins in cells and that the loss of either one will lead to the loss of the interacting partner. This observation explains the similar checkpoint phenotypes observed in both Tipin-and Timeless-depleted cells.DNA damage ͉ S phase ͉ cell cycle control ͉ circadian rhythms

show abstract

A time-less function for mouse Timeless

Cited by 163 publications

References 10 publications

Constructing a Feedback Loop with Circadian Clock Molecules from the Silkmoth, Antheraea pernyi

Constructing a Feedback Loop with Circadian Clock Molecules from the Silkmoth, Antheraea pernyi

Protumorigenic role of Timeless in hepatocellular carcinoma

Tipin and Timeless form a mutually protective complex required for genotoxic stress resistance and checkpoint function

Contact Info

Product

Resources

About