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In Vitro Bioluminescence Assay to Characterize Circadian Rhythm in Mammary Epithelial Cells
Published on: September 28, 2017
Clock genes and cancer
Patricia A Wood1, Xiaoming Yang, William J M Hrushesky
1Medical Chronobiology Laboratory, WJB Dorn VA Medical Center, School of Medicine, University of South Carolina, Columbia, SC 29209, USA. patricia.wood2@va.gov
Abstract:
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 beta-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal beta-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 beta-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 beta-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.
Insights
Period gene mutations disrupt circadian rhythms and promote unique cancer pathways by altering beta-catenin signaling and DNA damage response. These findings suggest PERIOD proteins as potential targets for cancer prevention.
Area of Science:
- Chronobiology
- Molecular Biology
- Oncology
Background:
- Period genes (Per2, Per1) are crucial circadian clock regulators and negative growth inhibitors.
- Mutations in Period genes are linked to epithelial hyperplasia, tumors, and impaired DNA damage response in mice and humans.
- Circadian disruption from factors like shift work is associated with increased cancer risk, but mechanisms remain unclear.
Purpose of the Study:
- To investigate the unique molecular pathways through which Period clock gene mutations promote tumorigenesis.
- To explore the role of Period genes in regulating beta-catenin and cell proliferation in various cancer types.
- To understand how intestinal tumorigenesis impacts clock gene function.
Main Methods:
- Analysis of Per2 mutant mice exhibiting de novo and radiation-induced tumors.
- Examination of human tumor samples for Period gene mutations or altered expression.
- Investigation of beta-catenin levels and cell proliferation in colon and non-colon cancer cells with Per2 mutations.
- Assessment of PER2 protein levels and circadian rhythms in Apc(Min/+) mouse intestines.
Main Results:
- Per2 mutations were associated with increased intestinal beta-catenin levels, colon polyp formation, and enhanced Apc(Min/+)-mediated tumorigenesis.
- Loss of PER2 protein and circadian rhythm abnormalities were observed in Apc(Min/+) mouse intestines.
- Specific alterations in intestinal clock gene and clock-controlled gene expression were identified in the context of tumorigenesis.
Conclusions:
- Period clock gene mutations uniquely promote tumorigenesis via altered beta-catenin signaling and DNA damage response pathways.
- Tumorigenesis can disrupt circadian clock function, as seen with increased beta-catenin destabilizing PER2 protein.
- PERIOD proteins represent promising novel targets for cancer prevention and therapeutic strategies.
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