Circadian expression of clock genes in human oral mucosa and skin: association with specific cell-cycle phases.
We studied the relative RNA expression of clock genes throughout one 24-hour period in biopsies obtained from the oral mucosa and skin from eight healthy diurnally active male study participants. We found that the human clock genes hClock, hTim, hPer1, hCry1, and hBmal1 are expressed in oral mucosa and skin, with a circadian profile consistent with that found in the suprachiasmatic nuclei and the peripheral tissues of rodents. hPer1, hCry1, and hBmal1 have a rhythmic expression, peaking early in the morning, in late afternoon, and at night, respectively, whereas hClock and hTim are not rhythmic. This is the first human study to show a circadian profile of expression for all five clock genes as documented in rodents, suggesting their functional importance in man. In concurrent oral mucosa biopsies, thymidylate synthase enzyme activity, a marker for DNA synthesis, had a circadian variation with peak activity in early afternoon, coinciding with the timing of S phase in our previous study on cell-cycle timing in human oral mucosa. The major peak in hPer1 expression occurs at the same time of day as the peak in G(1) phase in oral mucosa, suggesting a possible link between the circadian clock and the mammalian cell cycle.
Bjarnason
G A
GA
Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada. bjarnason@srcl.sunnybrook.utoronto.ca
Jordan
R C
RC
Wood
P A
PA
Li
Q
Q
Lincoln
D W
DW
Sothern
R B
RB
Hrushesky
W J
WJ
Ben-David
Y
Y
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins / Q000235:genetics; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D009061:Mouth Mucosa / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D017956:Photoreceptor Cells, Invertebrate; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D012867:Skin / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D029721:Drosophila Proteins; D005136:Eye Proteins; D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D013940:Thymidylate Synthase; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C539022:PER1 protein, human; C539023:Per1 protein, mouse; C509769:TIMELESS protein, human; C509770:Timeless protein, mouse; C119828:cry protein, Drosophila; C538943:CLOCK protein, human; C538944:Clock protein, mouse