Different roles of negative and positive components of the circadian clock in oncogene-induced neoplastic transformation

Chiharu Katamune, Satoru Koyanagi, Shoya Shiromizu, Naoya Matsunaga, Shigeki Shimba, Shigenobu Shibata, Shigehiro Ohdo

Research output: Contribution to journalArticle

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Abstract

In mammals, circadian rhythms in physiological function are generated by a molecular oscillator driven by transcriptional-translational feedback loop consisting of negative and positive regulators. Disruption of this circadian clock machinery is thought to increase the risk of cancer development, but the potential contributions of each component of circadian clock to oncogenesis have been little explored. Here we reported that negative and positive transcriptional regulators of circadian feedback loop had different roles in oncogene-induced neoplastic transformation. Mouse embryonic fibroblasts prepared from animals deficient in negative circadian clock regulators, Period2 (Per2) or Cryptochrome1/2 (Cry1/2), were prone to transformation induced by co-expression of H-rasV12 and SV40 large T antigen (SV40LT). In contrast, mouse embryonic fibroblasts prepared from mice deficient in positive circadian clock regulators, Bmal1 or Clock, showed resistance to oncogene-induced transformation. In Per2 mutant and Cry1/2-null cells, the introduction of oncogenes induced expression of ATF4, a potent repressor of cell senescence-associated proteins p16INK4a and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, in Bmal1-null and Clock mutant cells, the expression of ATF4 was not induced by oncogene introduction, which allowed constitutive expression of p16INK4a and p19ARF triggering cellular senescence. Although genetic ablation of either negative or positive transcriptional regulators of the circadian clock leads to disrupted rhythms in physiological functions, our findings define their different contributions to neoplastic cellular transformation.

Original languageEnglish
Pages (from-to)10541-10550
Number of pages10
JournalJournal of Biological Chemistry
Volume291
Issue number20
DOIs
Publication statusPublished - May 13 2016

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Circadian Clocks
Oncogenes
Clocks
Cell Aging
Fibroblasts
Cyclin-Dependent Kinase Inhibitor p16
Polyomavirus Transforming Antigens
Null Lymphocytes
Viral Tumor Antigens
Circadian Rhythm
Feedback
Mammals
Carcinogenesis
Ablation
Machinery
Animals
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Different roles of negative and positive components of the circadian clock in oncogene-induced neoplastic transformation. / Katamune, Chiharu; Koyanagi, Satoru; Shiromizu, Shoya; Matsunaga, Naoya; Shimba, Shigeki; Shibata, Shigenobu; Ohdo, Shigehiro.

In: Journal of Biological Chemistry, Vol. 291, No. 20, 13.05.2016, p. 10541-10550.

Research output: Contribution to journalArticle

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