title: Functional genomics identify Birc5/survivin as a candidate gene involved in the chronotoxicity of cyclin-dependent kinase inhibitors.
abstract: The circadian timing system orchestrates most of mammalian physiology and behavior in synchrony with the external light/dark cycle. This regulation is achieved through endogenous clocks present in virtually all body cells, where they control key cellular processes, including metabolism, transport, and the cell cycle. Consistently, it has been observed in preclinical cancer models that both the efficacy and toxicity of most chemotherapeutic drugs depend on their time of administration. To further explore the molecular basis underlying the link between the circadian timing system and the cellular response to anticancer drugs, we investigated the circadian transcriptome and CDK inhibitor toxicity in colon mucosa cells. We first show here that among 181 circadian transcripts, approximately 30% of them drive the cell cycle in the healthy mouse colon mucosa, with a majority peaking during the early resting phase. The identification of 26 mitotic genes within this cluster further indicated that the transcriptional coordination of mitosis by the circadian clock participates in the gating of cell division in this tissue. Subsequent selective siRNA-mediated silencing of these 26 targets revealed that low expression levels of the mitotic and anti-apoptotic gene Birc5/survivin significantly and specifically increased the sensitivity of colon epithelial cells to CDK inhibitors. By identifying Birc5/survivin as a potential determinant for the circadian modulation of CDK inhibitor toxicity, these data provide a mechanistic basis for the preclinical development of future CDK inhibitor-based chronotherapeutic strategies.
authors.affiliation: Institut de Biologie Valrose; Université Nice Sophia Antipolis; CNRS UMR7277; INSERM U1091; Nice, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Siffroi-Fernandez
authors.affiliation: INSERM U776 Rythmes biologiques et cancers; Villejuif, France; University Paris-Sud, Orsay; France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dulong
authors.affiliation: INSERM U776 Rythmes biologiques et cancers; Villejuif, France; University Paris-Sud, Orsay; France.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Li
authors.affiliation: INSERM U776 Rythmes biologiques et cancers; Villejuif, France; University Paris-Sud, Orsay; France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Filipski
authors.affiliation: Institut de Biologie Valrose; Université Nice Sophia Antipolis; CNRS UMR7277; INSERM U1091; Nice, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Gréchez-Cassiau
authors.affiliation: Institut de Biologie Valrose; Université Nice Sophia Antipolis; CNRS UMR7277; INSERM U1091; Nice, France.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Peteri-Brünback
authors.affiliation: CNRS; UPS2682; Station Biologique; Roscoff, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: INSERM U776 Rythmes biologiques et cancers; Villejuif, France; University Paris-Sud, Orsay; France; Assistance Publique-Hôpitaux de Paris; Unité de Chronothérapie; Département d'Oncologie Médicale; Hôpital Paul Brousse; Villejuif, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
authors.affiliation: Institut de Biologie Valrose; Université Nice Sophia Antipolis; CNRS UMR7277; INSERM U1091; Nice, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Teboul
authors.affiliation: Institut de Biologie Valrose; Université Nice Sophia Antipolis; CNRS UMR7277; INSERM U1091; Nice, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Delaunay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002940:Circadian Rhythm; D003106:Colon / Q000166:cytology / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000077546:Roscovitine; D000077022:Survivin; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases
keywords: Birc5; cell cycle; circadian clock; colon mucosa; cyclin-dependent kinase inhibitor; seliciclib