Activation of TGF-β/activin signalling resets the circadian clock through rapid induction of Dec1 transcripts

Kon, Naohiro; Hirota, Tsuyoshi; Kawamoto, Takeshi; Kato, Yukio; Tsubota, Tadashi; Fukada, Yoshitaka

doi:10.1038/ncb1806

Cited by 119 publications

(139 citation statements)

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“…Further investigation by us will be directed towards further addressing the mechanism. Kon et al (31) along with our previous study demonstrated that DEC1, as a downstream target gene, was induced by transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) (32). TNF-α and TGF-β were widely reported as regulators in epithelial-mesenchymal transition (EMT) through activation of NF-κB and TGF-β signal pathway, respectively (11,33).…”

Section: Discussionmentioning

confidence: 97%

DEC1 is positively associated with the malignant phenotype of invasive breast cancers and negatively correlated with the expression of claudin-1

Liu

Miao

Wang

et al. 2013

International Journal of Molecular Medicine

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Abstract. Differentiated embryo-chondrocyte expressed gene 1 (DEC1) is a basic helix-loop-helix transcriptional regulator, reportedly involved in cell growth, differentiation, apoptosis and tumorigenesis. In breast cancer, DEC1 expression correlates with increased malignant potential and invasiveness. Nevertheless, the detailed mechanisms by which DEC1 modulates breast cancer progression are still unclear. Claudin-1, an important tight junction protein, functions as a tumor invasion suppressor. In the present study, the relationship between DEC1 and claudin-1 in 147 cases of invasive breast ductal carcinomas was examined by immunohistochemistry. Based on the data, DEC1 expression was elevated in invasive breast ductal carcinomas and DEC1 levels were positively correlated with tumor grade (P=0.023). Moreover, DEC1 expression was negatively correlated with the claudin-1 level (correlation coefficient =-0.245, P=0.003). We further identified that, in MCF-7 and MDA-MB-231 breast cancer cell lines, DEC1 knockdown led to the enhanced expression of claudin-1 at both the mRNA and protein levels, and reduced cell invasive capacity. Collectively, our data suggest that overexpression of DEC1 may promote the invasiveness of breast cancer through downregulation of claudin-1. IntroductionDifferentiated embryo-chondrocyte expressed gene 1 (DEC1, also known as BHLHE40/Stra13/Sharp2) is a basic helix-loophelix (bHLH) transcription factor ubiquitously expressed in both embryonic and adult tissues (1,2). DEC1 exerts multiple biological functions, such as neurogenesis, apoptosis, cell proliferation, cell differentiation and circadian rhythms (3-8). Recent studies have revealed that the expression of DEC1 is correlated with the malignancy of a number of cancer types (9). The expression patterns of DEC1 and their impact on tumor development are largely tumor-type specific (1,9). Low DEC1 expression was found to be associated with poor histological differentiation and malignancy progression in hepatocellular carcinoma (10), whereas, overexpression of DEC1 was significantly correlated with poor survival of patients with esophageal squamous cell carcinoma following surgery (11). In breast cancer, the expression of DEC1 was found to be increased upon progression from normal tissues to invasive carcinomas (12). However, the mechanisms by which DEC1 modulates cancer progression are largely unclear.Claudin-1 is a key component of the tight junction complex and is thereby important for maintaining tight junction barrier integrity. Downregulation of claudin-1 is intimately associated with tumorigenesis in breast (13,14), prostate (15) and melanocytic neoplasia (16). It is postulated that the impact of claudin-1 on cancer invasion and metastasis is through its regulation of certain invasion/metastasis suppressors or enhancers (17,18). As significant loss of claudin-1 expression and overexpression of DEC1 are commonly observed in the progression of various types of cancers including breast cancer, we aimed to ascertain whether DEC1 modulates br...

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Section: Discussionmentioning

confidence: 97%

DEC1 is positively associated with the malignant phenotype of invasive breast cancers and negatively correlated with the expression of claudin-1

Liu

Miao

Wang

et al. 2013

International Journal of Molecular Medicine

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“…7, E-K), suggesting that BMAL2 plays a more important role in a regulatory loop than that in the core loop. Bmal2 might be an important gene as well for clock resetting, like Dec1 (29).…”

Section: Discussionmentioning

confidence: 99%

Preferential Inhibition of BMAL2-CLOCK Activity by PER2 Reemphasizes Its Negative Role and a Positive Role of BMAL2 in the Circadian Transcription

Sasaki

Yoshitane

et al. 2009

Journal of Biological Chemistry

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In the molecular oscillatory mechanism governing circadian rhythms, positive regulators, including CLOCK and BMAL1, transactivate Per and Cry genes through E-box elements, and translated PER and CRY proteins negatively regulate their own transactivation. Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription, but the role of BMAL2 in the circadian clockwork is still elusive. Here we characterized BMAL2 function in NIH3T3 cells and found that the cellular rhythms monitored by Bmal1 promoterdriven bioluminescence signals were blunted by RNA interference-mediated suppression of Bmal2 as well as that of Bmal1. Transcription assays with a 2.1-kb mPer1 promoter revealed that CRY2 inhibited the transactivation mediated by BMAL1-CLOCK more strongly than that by BMAL2-CLOCK. In contrast, PER2 showed a stronger inhibitory effect on BMAL2-CLOCK than on BMAL1-CLOCK. The molecular link between BMAL2 and PER2 was further strengthened by the fact that PER2 exhibited a greater affinity for BMAL2 than for BMAL1 in co-immunoprecipitation experiments. These results indicate a functional partnership between BMAL2 and PER2 and reemphasize the negative role of PER2 in the circadian transcription. As a broad spectrum function, BMAL2-CLOCK activated transcription from a variety of SV40-driven reporters harboring various E/E-box-containing sequences present in the upstream regions of clock and clock-controlled genes. Importantly, the efficiencies of BMAL2-CLOCK-mediated transactivation relative to that achieved by BMAL1-CLOCK were dependent heavily on the E-box-containing sequences, supporting distinguishable roles of the two BMALs. Collectively, it is strongly suggested that BMAL2 plays an active role in the circadian transcription.A variety of organisms from bacteria to humans show circadian rhythms in physiology and behavior under the regulation of endogenous circadian clocks oscillating with an ϳ24-h periodicity (1, 2). In mammals, the central clock is located in the hypothalamic suprachiasmatic nucleus, whereas peripheral clocks with self-sustainable oscillation machinery are located in many peripheral tissues (3). Even cultured fibroblasts were shown to retain the cellular clocks (4), and hence they have been used for studies on the oscillatory mechanism of peripheral clocks. The molecular clockwork in mammals centers on transcription/translation-based autoregulatory feedback loops of clock genes, to which bHLH 3 -PAS proteins, BMAL1 and CLOCK, contribute as positive regulators of the transcription (2, 5). BMAL1-CLOCK complex activates transcription through CACGTG-type E-box and its related sequences found in promoter regions of clock genes and clock-controlled genes such as Per1 (6), Per2 (CACGTT E-box-like or EЈ-box sequence; see Ref. 7), plasminogen activator inhibitor-1 (PAI-1) (8), and Rev-Erb␣/␤ (9, 10). The E-box-dependent transactivation mediated by the BMAL1-CLOCK complex is suppressed by an expanding number of negative regulators, including PER1 (11, 12), PER2 (13-15), PER3 (16,1...

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“…[47][48][49][50] Conversely, several studies have demonstrated at a molecular level how these intracellular signaling mediators contribute to circadian regulation. For example, in mammals, glycogen synthase kinase-3b (GSK-3b), the key kinase regulating the Wnt signaling pathway, phosphorylates CRY2 and PER2 and thereby controls CRY2 protein stability and PER2 subcellular localization.…”

Section: Possible Crosstalk Between the Circadian Clock And Cellular mentioning

confidence: 99%

“…48,51) Another example is the stimulation of Dec1 gene expression that is induced by the TGF-b/activin signaling pathway during alkaline shockinduced entrainment of mammalian peripheral clocks. 49) The signaling pathways involving these mediators play essential roles in development, proliferation, DDR, and cell death processes, suggesting that these processes and the circadian clock are separate nodes of a common regulatory network. In support of this idea, a recent study in zebrafish has revealed that the same MAPK signaling cascades are involved in both DDR and the light-dependent pathways responsible for entrainment of the circadian clock 52) (see below).…”

Section: Possible Crosstalk Between the Circadian Clock And Cellular mentioning

confidence: 99%

A Common Origin: Signaling Similarities in the Regulation of the Circadian Clock and DNA Damage Responses

Uchida

Hirayama

Nishina

2010

Biological & Pharmaceutical Bulletin

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INTRODUCTIONFrom bacteria to humans, almost all organisms can adapt the timing of their physiology to the cyclic changes of their environment, thanks to a naturally-selected intrinsic timekeeping system called the circadian clock. 1) The circadian clock enhances the physiological efficiency and survival of an organism by organizing its behavior and body functions. 2,3) During the circadian day, the organism's physiology is given over to catabolic processes, whereas the anabolic functions of growth, repair and consolidation occur at night. To achieve this schedule in mammals, the circadian clock regulates a number of physiological functions, including sleep and wakefulness, food intake, body temperature, cardiovascular and renal activity, hormone production, hepatic metabolism and immune responses. 4,5) Accordingly, disruption of the circadian clock in humans has been linked to profound effects on health, including insomnia, stomach ailments, depression and cancer. 4,5) In most organisms, the molecular mechanisms underlying the establishment and maintenance of biological rhythms comprise interconnected transcription-translation feedback loops in which some clock factors repress their own transcription once they have attained critical levels. 2,3) These oscillators have the property of being endogenous and cellautonomous systems that maintain their rhythm in the absence of external time cues. 6) Both vertebrates and invertebrates have circadian oscillators scattered throughout their bodies. 7,8) In mammals, the circadian system is composed of both central and peripheral oscillators. 7) The mammalian central clock is located in the suprachiasmatic nucleus (SCN) within the anterior hypothalamus of the brain. 9) This central clock acts as a coordinator and provides time signals via both neural and humoral routes that entrain independent peripheral clocks. Dysfunction of the central clock does not inactivate the peripheral clocks but instead causes individual peripheral oscillators to become temporally uncoupled. [10][11][12] To guarantee that an organism's behavior remains tied to the rhythms of its environment, the circadian clock must be able to reset itself in response to environmental cues. 9,13,14) The main environmental stimulus for organisms is light, which is provided in day-night cycles. Mammals have no photoreceptors in peripheral tissues, 15) so that the effect of light on peripheral clocks is indirect. 13) For the mammalian clock, the SCN integrates photic cues from the retina and uses neural and humoral signals to transmit this information to peripheral clocks, synchronizing them. [16][17][18] This communication between the central and peripheral clocks results in the seamless regulation of fundamental physiological functions. 4,8) Interestingly, peripheral clocks can also respond directly to SCN-independent signals such as feeding and temperature change. 19,20) However, the physiological role of SCN-independent responses of peripheral clocks is not yet fully understood. A recent study has reported that ...

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Activation of TGF-β/activin signalling resets the circadian clock through rapid induction of Dec1 transcripts

Cited by 119 publications

References 35 publications

DEC1 is positively associated with the malignant phenotype of invasive breast cancers and negatively correlated with the expression of claudin-1

DEC1 is positively associated with the malignant phenotype of invasive breast cancers and negatively correlated with the expression of claudin-1

Preferential Inhibition of BMAL2-CLOCK Activity by PER2 Reemphasizes Its Negative Role and a Positive Role of BMAL2 in the Circadian Transcription

A Common Origin: Signaling Similarities in the Regulation of the Circadian Clock and DNA Damage Responses

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