Dysfunction of the circadian transcriptional factor CLOCK in mice resists chemical carcinogen-induced tumorigenesis
| Autor: | Shigehiro Ohdo, Ken ichi Hashikawa, Satoru Koyanagi, Naoki Kusunose, Chiharu Katamune, Naoya Matsunaga |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Skin Neoplasms DNA damage Carcinogenesis Circadian clock lcsh:Medicine CLOCK Proteins Biology medicine.disease_cause Article Gene product 03 medical and health sciences Epidermal growth factor Internal medicine medicine Animals Circadian rhythm lcsh:Science Mice Knockout Mice Inbred ICR Multidisciplinary lcsh:R Cell biology CLOCK Disease Models Animal 030104 developmental biology Endocrinology Carcinogens lcsh:Q Female Signal transduction |
| Zdroj: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
| ISSN: | 2045-2322 |
| Popis: | The chronic disruption of circadian rhythms has been implicated in the risk of cancer development in humans and laboratory animals. The gene product CLOCK is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in various physiological processes. However, we demonstrated here that Clk/Clk mice resisted chemical carcinogen-induced tumorigenesis by suppressing epidermal growth factor (EGF) receptor-mediated proliferation signals. The repetitive application of 7,12-dimethylbenz[α]anthracene (DMBA) to skin on the back resulted in the significant development of tumors in wild-type mice, whereas chemically-induced tumorigenesis was alleviated in Clk/Clk mice. Although the degree of DMBA-induced DNA damage was not significantly different between wild-type and Clk/Clk mice, EGF receptor-mediated Ras activation was not detected in DMBA-treated Clk/Clk mice. Genetic and biochemical experiments revealed that the suppression of EGF receptor-mediated signal transduction in DMBA-treated Clk/Clk mice was associated with the expression of the cellular senescence factor p16INK4a. These results suggest an uncovered role for CLOCK in the development of chemical carcinogen-induced primary tumors and offers new preventive strategies. |
| Databáze: | OpenAIRE |
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