Circadian gene <i>mPer2</i> overexpression induces cancer cell apoptosis

Hua, Hui; Wang, Yueqi; Wan, Chaomin; Liu, Yanyou; Zhu, Bin; Yang, Cheng; Wang, Xiaojia; Wang, Zhengrong; Cornelissen-Guillaume, Germaine G; Halberg, Franz

doi:10.1111/j.1349-7006.2006.00225.x

Cited by 194 publications

(189 citation statements)

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“…In particular, c-Myc is controlled by Per2 through the activity of Bmal1/clock heterodimers (19). overexpression of the Per2 gene induces cancer cell apoptosis (20), and inhibits the neoplastic growth of cancer cells (30). Moreover, Per2 gene mutations have been identified in human colorectal and breast cancers (31), and overexpression of per2 inhibits tumor proliferation in culture as well as in animals (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, overexpression of per1 in prostate cancer cells causes significant growth inhibition and apoptosis (18). In addition, per2 plays a key role in tumor suppression, controlled by genes such as c-myc and cyclin D1 through the activity of Bmal1/clock heterodimers (19), and Per2 gene overexpression induces cancer cell apoptosis (20). per2 overexpression has also been found to inhibit the growth of pancreatic cancer cells and to act synergistically with cisplatin (21).…”

Section: Introductionmentioning

confidence: 99%

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Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer

Oshima

2011

Oncol Rep

100

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Abstract. circadian rhythms are daily oscillations in various biological processes, generated by the feedback loops of eight core circadian genes: Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmal1 and Casein Kinase I ε (CKIε). recent studies have suggested that circadian genes participate in the growth and development of various cancers. this study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. the relative expression levels of the circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. expression of the Clock gene and the CKIε gene in cancer tissue were significantly higher compared to that in adjacent normal mucosa. expression of the Per1 and Per3 genes in cancer tissue was significantly lower compared to that in adjacent normal mucosa. Analysis of the relations between clinicopathological features and expression of the eight circadian genes in cancer tissue showed that high expression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. on analysis of the relations between outcomes and gene expression, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene. overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer. Introductioncircadian rhythms are daily oscillations in various biologic processes. In mammals, the master circadian pacemaker is located in the suprachiasmatic nuclei (scn) (1). the master circadian clock coordinates peripheral circadian clocks within virtually every cell in the body (2). this coordination is accomplished directly through autonomic nervous system innervation and indirectly through daily rhythmic synthesis and release of an array of hypothalamic, pituitary, and dispersed endocrine hormones (3-6). the molecular mechanism of circadian oscillation in the scn and peripheral cells is based on the feedback loops of eight core circadian genes (3,7,8). these eight genes are Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmal1, and Casein Kinase I ε (CKIε). the feedback loops of the eight core circadian genes are as follows. the Clock gene remains steady throughout the 24-h day. High levels of Bmal1 promote the formation of Bmal1/clock heterodimers. these heterodimers bind to e-box sequences in the promoters of the Cry and Per genes to activate transcription. Bmal1/clock heterodimers can also inhibit Bmal1 transcription. After transcription and translation, the per proteins accumulate in the cytoplasm and are phosphorylated by...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer

Oshima

2011

Oncol Rep

100

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“…For example, mPer2 expression has been recently related with tumor suppression because overexpression of Per2 in some mouse carcinoma cell lines results in reduced cellular proliferation and rapid apoptosis. 36 Moreover, in humans, long-term shift work and frequent traveling between time zones have been associated with marked disturbances of the internal daily metabolic cycles and neurological, gastrointestinal and cardiovascular diseases. 37 Indeed, in the present work, clock genes expression in the subcutaneous fat was associated to total and LDL cholesterol, suggesting that in these morbid obese patients, the different clock genes are related to the disturbances associated to obesity.…”

Section: Discussionmentioning

confidence: 99%

Clock genes are implicated in the human metabolic syndrome

et al. 2007

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Background: Clock genes play a role in adipose tissue (AT) in animal experimental models. However, it remains to be elucidated whether these genes are expressed in human AT. Objective: We investigated the expression of several clock genes, Bmal1, Per2 and Cry1, in human AT from visceral and subcutaneous abdominal depots. A second objective was to elucidate whether these clock genes expressions were related to the metabolic syndrome features. Methods: Visceral and subcutaneous AT samples were obtained from morbid obese men (n ¼ 8), age: 42713 years and body mass indexX40 kg/m 2 , undergoing laparoscopic surgery due to obesity. Biopsies were taken as paired samples at the beginning of the surgical process (1100 hour). Metabolic syndrome features such as waist circumference, plasma glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein (LDL) cholesterol were also studied. Homeostasis model assessment index of insulin resistance was also calculated. The expression of the different clock genes, hBmal1, hPer2 and hCry1, was determined by quantitative real-time PCR. Results: Clock genes were expressed in both human AT depots. hBmal1 expression was significantly lower than hPer2 and hCry1 in both AT (Po0.001). All genes were highly correlated to one another in the subcutaneous fat, while no correlation was found between Bmal1 and Per2 in the visceral AT. Clock genes AT expression was associated with the metabolic syndrome parameters: hPer2 expression level from visceral depot was inversely correlated to waist circumference (Po0.01), while the three clock genes studied were significantly and negatively correlated to total cholesterol and LDL cholesterol (Po0.01). Conclusion: We have demonstrated for the first time in humans that clock genes are expressed in both subcutaneous and visceral fat. Their association with abdominal fat content and cardiovascular risk factors may be an indicator of the potential role of these clock genes in the metabolic syndrome disturbances.

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“…The increased proliferation and decreased apoptosis that are associated with clock disruption in tumors can be reverted through overexpressing Per1 or Per2 in malignant cells (Gery et al 2006;Hua et al 2006Hua et al , 2007. Thus, overexpression of Per1-sensitized human cancer cells to lowdose radiation that produced DNA-damage-induced apoptosis, whereas inhibition of Per1 cells blunted apoptosis in these tumor cells (Gery et al 2006).…”

Section: Interactions Between Molecular Clock and Cellular Proliferationmentioning

confidence: 99%

Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

Lévi

Filipski²,

Iurisci³

et al. 2007

Cold Spring Harbor Symposia on Quantitative Biology

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Circadian gene mPer2 overexpression induces cancer cell apoptosis

Cited by 194 publications

References 30 publications

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer

Clock genes are implicated in the human metabolic syndrome

Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

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