THE CIRCADIAN CLOCK GENE<i>PER1</i>SUPPRESSES CANCER CELL PROLIFERATION AND TUMOR GROWTH AT SPECIFIC TIMES OF DAY

Yang, Xiaoming; Wood, Patricia A.; Ansell, Christine; Quiton, Dinah Faith T; Oh, Eunsun; Du-Quiton, Jovelyn; Hrushesky, William J. M.

doi:10.3109/07420520903431301

Cited by 106 publications

(105 citation statements)

References 34 publications

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“…Downregulation of PER1 in tumors, similar to the results with PER2, also increases breast cancer growth in vivo. 38 Therefore, it appears that both PERIOD proteins, PER2 and PER1, can modulate β-catenin and consequently alter cell growth, and these effects are not dependent on an underlying, aberrant Apc-β-catenin pathway.…”

Section: Loss Of Per1 Results In Similar Effectsmentioning

confidence: 99%

Clock Genes and Cancer

2009

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Period genes (Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased cancer risk. The mechanisms responsible for the connection between the circadian clock and cancer are not well defined. We propose that circadian disruption per se is not uniformly tumor promoting and the mechanisms for tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote tumorigenesis by unique molecular pathways. Per2 and Per1 modulate β-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal β-catenin levels and colon polyp formation. Per2 mutation also increases Apc Min/+ -mediated intestinal and colonic polyp formation. Intestinal tumorigenesis per se may also alter clock function as a result of increased β-catenin destabilizing PER2 protein. Levels and circadian rhythm of PER2 in Apc Min/+ mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that tumor promotion by loss of PERIOD clock proteins is unique to these clock genes as a result of altered β-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.

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Section: Loss Of Per1 Results In Similar Effectsmentioning

confidence: 99%

Clock Genes and Cancer

2009

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“…In the first study, rats displayed altered circadian rhythm characteristics (acrophase, amplitude, and mesor values) of (131,194,202) (30,99,132,193,197) 33,60,65,79,199 126,198) Arrows indicate direction of expression or activity change of the component; = indicates no change from control. CAT, catalase; CLOCK, circadian locomotor output cycles kaput protein; GSH, glutathione; NSCL, non-small cell lung; PER, periods.…”

Section: Cancermentioning

confidence: 99%

Circadian Rhythm Connections to Oxidative Stress: Implications for Human Health

Wilking

Ndiaye²,

Mukhtar³

et al. 2013

Antioxidants & Redox Signaling

246

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Significance: Oxygen and circadian rhythmicity are essential in a myriad of physiological processes to maintain homeostasis, from blood pressure and sleep/wake cycles, down to cellular signaling pathways that play critical roles in health and disease. If the human body or cells experience significant stress, their ability to regulate internal systems, including redox levels and circadian rhythms, may become impaired. At cellular as well as organismal levels, impairment in redox regulation and circadian rhythms may lead to a number of adverse effects, including the manifestation of a variety of diseases such as heart diseases, neurodegenerative conditions, and cancer. Recent Advances: Researchers have come to an understanding as to the basics of the circadian rhythm mechanism, as well as the importance of the numerous species of oxidative stress components. The effects of oxidative stress and dysregulated circadian rhythms have been a subject of intense investigations since they were first discovered, and recent investigations into the molecular mechanisms linking the two have started to elucidate the bases of their connection. Critical Issues: While much is known about the mechanics and importance of oxidative stress systems and circadian rhythms, the front where they interact has had very little research focused on it. This review discusses the idea that these two systems are together intricately involved in the healthy body, as well as in disease. Future Directions: We believe that for a more efficacious management of diseases that have both circadian rhythm and oxidative stress components in their pathogenesis, targeting both systems in tandem would be far more successful.

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“…In animal models, Per1 has a tumor suppressor function that, however, is exerted only at certain circadian stages. Down-regulation of Per1 leads to augmented tumor growth through an increase in the amplitude of the circadian peaks in tumor cell proliferation (76).…”

Section: Circadian Clock and Cell Cyclementioning

confidence: 99%