Altered Stra13 and Dec2 circadian gene expression in hypoxic cells.
The circadian system regulates rhythmically most of the mammalian physiology in synchrony with the environmental light/dark cycle. Alteration of circadian clock gene expression has been associated with tumour progression but the molecular links between the two mechanisms remain poorly defined. Here we show that Stra13 and Dec2, two circadian transcriptional regulators which play a crucial role in cell proliferation and apoptosis are overexpressed and no longer rhythmic in serum shocked fibroblasts treated with CoCl(2,) a substitute of hypoxia. This effect is associated with a loss of circadian expression of the clock genes Rev-erbalpha and Bmal1, and the clock-controlled gene Dbp. Consistently, cotransfection assays demonstrate that STRA13 and DEC2 both antagonize CLOCK:BMAL1 dependent transactivation of the Rev-erbalpha and Dbp promoters. Using a transplantable osteosarcoma tumour model, we show that hypoxia is associated with altered circadian expression of Stra13, Dec2, Rev-erbalpha, Bmal1 and Dbp in vivo. These observations collectively support the notion that overexpression of Stra13 and Dec2 links hypoxia signalling to altered circadian clock gene expression.
Guillaumond
Fabienne
F
Université de Nice-Sophia Antipolis, CNRS FRE3094, 28 Av. Valrose, 06108 Nice, France.
Lacoche
Samuel
S
Dulong
Sandrine
S
Grechez-Cassiau
Aline
A
Filipski
Elisabeth
E
Li
Xiao-Mei
XM
Lévi
Francis
F
Berra
Edurne
E
Delaunay
Franck
F
Teboul
Michèle
M
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics*; D056926:CLOCK Proteins; D015687:Cell Hypoxia / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics*; D003035:Cobalt / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D012516:Osteosarcoma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D003035:Cobalt; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051793:Hypoxia-Inducible Factor 1; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C470968:Bhlhb3 protein, mouse; C491539:Bhlhe40 protein, mouse; C498260:Dbp protein, mouse; C498262:Nr1d1 protein, mouse; C538944:Clock protein, mouse; C018021:cobaltous chloride