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CC BY V4.0, Open Access
Journal article
G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment
PLoS biology, Vol.17(4), pp.e3000228-e3000228
04/30/2019
PMID: 31039152
Abstract
Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unknown. To address such mechanisms, we subjected transformed cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag scheme, and assayed a range of cellular functions. The results indicated a specific circadian clock-dependent increase in cell proliferation. Transcriptome analysis revealed up-regulation of G1/S phase transition genes (myelocytomatosis oncogene cellular homolog [Myc], cyclin D1/3, chromatin licensing and DNA replication factor 1 [Cdt1]), concomitant with increased phosphorylation of the retinoblastoma (RB) protein by cyclin-dependent kinase (CDK) 4/6 and increased G1-S progression. Phospho-RB (Ser807/811) was found to oscillate in a circadian fashion and exhibit phase-shifted rhythms in circadian desynchronized cells. Consistent with circadian regulation, a CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day-specific manner. Our study identifies a mechanism that underlies effects of circadian disruption on tumor growth and underscores the use of treatment timed to endogenous circadian rhythms.
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Details
- Title
- G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment
- Creators
- Yool Lee - Washington State University, Biomedical Sciences, Department ofNicholas F. Lahens - Translational TherapeuticsShirley Zhang - Howard Hughes Medical InstituteJoseph Bedont - Howard Hughes Medical InstituteJeffrey M. Field - Translational TherapeuticsAmita Sehgal - University of Pennsylvania
- Publication Details
- PLoS biology, Vol.17(4), pp.e3000228-e3000228
- Academic Unit
- Elson S. Floyd College of Medicine
- Publisher
- Public Library Science
- Number of pages
- 33
- Grant note
- R37NS048471 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R37-NS-048471 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Howard Hughes Medical Institute (HHMI); Howard Hughes Medical Institute
- Identifiers
- 99901132535701842
- Language
- English
- Resource Type
- Journal article