LARK activates posttranscriptional expression of an essential mammalian clock protein, PERIOD1.
The mammalian molecular clock is composed of feedback loops to keep circadian 24-h rhythms. Although much focus has been on transcriptional regulation, it is clear that posttranscriptional controls also play important roles in molecular circadian clocks. In this study, we found that mouse LARK (mLARK), an RNA binding protein, activates the posttranscriptional expression of the mouse Period1 (mPer1) mRNA. A strong circadian cycling of the mLARK protein is observed in the suprachiasmatic nuclei with a phase similar to that of mPER1, although the level of the Lark transcripts are not rhythmic. We demonstrate that LARK causes increased mPER1 protein levels, most likely through translational regulation and that the LARK1 protein binds directly to a cis element in the 3' UTR of the mPer1 mRNA. Alterations of mLark expression in cycling cells caused significant changes in circadian period, with mLark knockdown by siRNA resulting in a shorter circadian period, and the overexpression of mLARK1 resulting in a lengthened period. These data indicate that mLARKs are novel posttranscriptional regulators of mammalian circadian clocks.
Kojima
Shihoko
S
Laboratory of Chronogenomics, Mitsubishi Kagaku Institute of Life Sciences, Minamiooya, Machida, Tokyo, Japan.
Matsumoto
Ken
K
Hirose
Matsumi
M
Shimada
Miyuki
M
Nagano
Mamoru
M
Shigeyoshi
Yasufumi
Y
Hoshino
Shin-ichi
S
Ui-Tei
Kumiko
K
Saigo
Kaoru
K
Green
Carla B
CB
Sakaki
Yoshiyuki
Y
Tei
Hajime
H
D000595:Amino Acid Sequence; D000818:Animals; D001683:Biological Clocks / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics*; D056950:Period Circadian Proteins; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; C518159:LARK protein, mouse; D009687:Nuclear Proteins; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D016601:RNA-Binding Proteins