Mammalian <i>Clock</i> Gene <i>Cryptochrome</i> Regulates Arthritis via Proinflammatory Cytokine TNF-α

Hashiramoto, Akira; Yamada, Takashi; Tsumiyama, Ken; Yoshida, Kohsuke; Komai, Koichiro; Yamada, Hiroyuki; Yamazaki, Fumiyoshi; Doi, Masao; Okamura, Hitoshi; Shiozawa, Shunichi

doi:10.4049/jimmunol.0903284

Cited by 158 publications

(157 citation statements)

References 29 publications

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“…Hashiramoto et al has also previously shown high expression of TNF-α in Cry1 −/− ;Cry2 −/− fibroblasts (35). We also observed increased phospho-IKK2 in Cry1 −/− ;Cry2 −/− fibroblasts (Fig.…”

Section: Discussionsupporting

confidence: 72%

Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines

Narasimamurthy

Hatori

Nayak

et al. 2012

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

345

264

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Chronic sleep deprivation perturbs the circadian clock and increases susceptibility to diseases such as diabetes, obesity, and cancer. Increased inflammation is one of the common underlying mechanisms of these diseases, thus raising a hypothesis that circadianoscillator components may regulate immune response. Here we show that absence of the core clock component protein cryptochrome (CRY) leads to constitutive elevation of proinflammatory cytokines in a cell-autonomous manner. We observed a constitutive NF-κB and protein kinase A (PKA) signaling activation in Cry1 −/− ; Cry2 −/− cells. We further demonstrate that increased phosphorylation of p65 at S276 residue in Cry1 −/− ;Cry2 −/− cells is due to increased PKA signaling activity, likely induced by a significantly high basal level of cAMP, which we detected in these cells. In addition, we report that CRY1 binds to adenylyl cyclase and limits cAMP production. Based on these data, we propose that absence of CRY protein(s) might release its (their) inhibition on cAMP production, resulting in elevated cAMP and increased PKA activation, subsequently leading to NF-κB activation through phosphorylation of p65 at S276. These results offer a mechanistic framework for understanding the link between circadian rhythm disruption and increased susceptibility to chronic inflammatory diseases.biological clock | immune system I n response to the rotation of the earth, many of the mammalian physiological processes such as sleep-wake cycle and feeding pattern undergo an ∼24-h oscillation referred as the circadian clock. Circadian oscillation helps organisms anticipate and adapt to predictable daily changes in the environment. The hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian oscillator, which controls behaviors. At molecular level, the circadian oscillator is based on a cell-autonomous transcription-translation feedback loop, in which transcriptional activators circadian locomotor output cycles kaput (CLOCK)/brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like (BMAL)1 activate the expression of Cryptochrome (Cry) and Period (Per), in turn their protein products repress BMAL1 and CLOCK activity, thus producing Cry and Per expression rhythms (1, 2). Reverse orientation c-erb (REV-ERB)s and RAR-related orphan receptor (ROR)s also participate in the rhythmic transcriptional activity of the molecular oscillator (3). Molecular components of the circadian clock network are conserved in the SCN and also in peripheral cells. The oscillator uses direct and indirect mechanisms to impose rhythms and regulate several physiological processes, such as rest-activity cycle, endocrine system, and metabolism (4).Sleep loss or chronic sleep deprivation disrupts the circadian rhythm. It has been reported that people exposed to constant circadian disruption, such as shift-workers, show increased incidence of chronic diseases such as diabetes, obesity, and also cancer (5-7). Chronic inflammation is one of the important pathogenic features of these di...

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Section: Discussionsupporting

confidence: 72%

Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines

Narasimamurthy

Hatori

Nayak

et al. 2012

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

345

264

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“…We believe that our data in this paper have provided a plausible explanation: The clock disruption through CRY mutation sensitizes the transformed cells to apoptosis by inflammatory cytokines such as TNFα, which is known to be elevated in CRY mutant mice (30). Our findings also link two major signaling pathways, the circadian clock, which introduces a temporal variable into many cellular and physiological functions, and the NF-κB pathway, which is a key nodal focus in the inflammatory response at a cellular and organismal level.…”

Section: Resultsmentioning

confidence: 99%

Regulation of apoptosis by the circadian clock through NF-κB signaling

Lee

Sancar

2011

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

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In mice and humans the circadian rhythm of many biochemical reactions, physiology, and behavior is generated by a transcriptionaltranslation feedback loop (TTFL) made up of the so-called core clock genes/proteins. The circadian system interfaces with most signaling pathways including those involved in cell proliferation and inflammation. Cryptochrome (CRY) is a core clock protein that plays an essential role in the repressive arm of the TTFL. It was recently reported that mutation of CRY in p53-null mice delayed the onset of cancer. It was therefore suggested that CRY mutation may activate p53-independent apoptosis pathways, which eliminate premalignant and malignant cells and thus delay overt tumor formation. Here we show that CRY mutation sensitizes p53 mutant and oncogenically transformed cells to tumor necrosis factor α (TNFα)-initiated apoptosis by interfacing with the NF-κB signaling pathway through the GSK3β kinase and alleviating prosurvival NF-κB signaling. These findings provide a mechanistic foundation for the delayed onset of tumorigenesis in clock-disrupted p53 mutant mice and suggest unique therapeutic strategies for treating cancers associated with p53 mutation. hepatocellular carcinoma | inflammatory cytokine | extrinsic apoptotic pathway T he circadian rhythm in mammalian organisms is generated by a molecular clock comprising four gene/protein groups (1-5): The CLOCK (NPAS2) and BMAL1 transactivators and the cryptochrome 1 and 2 (CRY1/2) and the period 1 and 2 (PER1/ 2) repressors. CLOCK (or NPAS2) and BMAL1 make heterodimers, which act on the promoters of CRY1/2 and PER1/2 and activate their transcription. The CRY and PER proteins in turn, after a time delay of ill-defined mechanism, inhibit the CLOCK-BMAL1 transactivator and hence their own transcription to close the TTFL. This core TTFL directly or indirectly affects most cellular functions, and as a result, clock disruption by core clock gene mutation is expected to have serious repercussions at the cellular and organismal levels.We recently reported that mice of the p53 −/− Cry1 −/− Cry −/− (hereafter p53 KO Cry DKO ) genotype exhibited delayed onset of spontaneous cancer relative to p53 −/− (p53 KO ) mice (6). When analyzed for their response to genotoxic stress, it was found that p53 KO Cry DKO cells were more sensitive to UV-induced apoptosis than p53 KO cells even though they are identical in terms of DNA repair and DNA damage checkpoint functions (6). Therefore, we ascribed the reduced clonogenic survival of p53 KO Cry DKO cells upon UV irradiation, relative to p53 KO cells, to enhanced p53-independent apoptosis as a consequence of CRY mutation. We also suggested that the delayed onset of cancer and prolonged lifespan of mice of p53 KO Cry DKO genotype may have been caused by enhanced apoptosis of oncogenically transformed cells before giving rise to macroscopic tumors (6). In line with these findings we recently determined that p53 KO Cry DKO tumors are more responsive to oxaliplatin than p53 KO tumors (7). However, UV and oxaliplatin...

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“…In a model of collagen induced arthritis (CIA), mice lacking CRY1 and CRY2 display greater levels of TNF␣ and have heightened inflammation in their joints versus wild-type mice [146]. By ectopically expressing CRY1 in MEFs isolated from Cry1/Cry2 −/-mice, activation of a TNF␣ luciferase promoter was vastly decreased.…”

Section: The Clock Repressors: Period and Cryptochromementioning

confidence: 97%

“…[66,116] Clock 19 Global • Obese and display impaired glucose sensitivity with insulin resistance and reduced islet size [112,113] • Increased plasma triglyceride and glucose levels [85,114] • Increased fibrotic damage in model of pulmonary fibrosis [87] • Impaired anti-oxidant defense [87] Cry1/Cry2 Global • Increased NAD+ and ATP. Decreased lactate and triglycerides in MEFs [95] • Greater inflammatory damage in CIA model [146] • Increased Cxcl1. Il-6 and Tnf˛ RNA.…”

Section: Bmal1-a Master Regulatormentioning

confidence: 99%