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The timing of mammalian circadian rhythm is determined by interlocking negative and positive transcriptional feedback loops that govern the cyclic expression of both clock regulators and output genes. In mammals, nuclear localization of the circadian regulators PER1-3 is controlled by multiple mechanisms, including multimerization with PER and CRY proteins. In addition, nuclear entry of mammalian PER1 (mPER1) can be regulated by a phosphorylation-dependent masking of its nuclear localization signal. Here we present evidence suggesting that nuclear localization of PER proteins is a dynamic process determined by both nuclear import and previously unrecognized nuclear export pathways. Examination of the subcellular localization of a series of truncated mPER1 proteins demonstrated that cytoplasmic localization is mediated by an 11-amino acid region with homology to leucine-rich nuclear export signals (NESs). Similar sequences were identified in mPER2 and mPER3 as well as in several insect PER proteins. The putative NESs from mPER1 and mPER2 were able to direct cytoplasmic accumulation when fused to a heterologous protein. Mutations in conserved NES residues and the nuclear export inhibitor leptomycin B each blocked the function of the NES. Full-length mPER1 was also exported from microinjected Xenopus laevis oocyte nuclei in an NES-dependent manner. The presence of a functional NES in mPER1 and mPER2 as well as related sequences in a variety of other PER proteins suggests that nuclear export may be a conserved and important feature of circadian regulators.
Albrecht,
A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light.
1997, Pubmed
Albrecht,
A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light.
1997,
Pubmed Bae,
Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock.
2001,
Pubmed Curtin,
Temporally regulated nuclear entry of the Drosophila period protein contributes to the circadian clock.
1995,
Pubmed Dunlap,
Molecular bases for circadian clocks.
1999,
Pubmed Eide,
Casein kinase I: another cog in the circadian clockworks.
2001,
Pubmed Field,
Analysis of clock proteins in mouse SCN demonstrates phylogenetic divergence of the circadian clockwork and resetting mechanisms.
2000,
Pubmed Fukuda,
CRM1 is responsible for intracellular transport mediated by the nuclear export signal.
1997,
Pubmed
,
Xenbase Gerace,
Nuclear export signals and the fast track to the cytoplasm.
1995,
Pubmed Kume,
mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop.
1999,
Pubmed Lowrey,
Genetics of the mammalian circadian system: Photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation.
2000,
Pubmed Mowen,
Regulation of STAT1 nuclear export by Jak1.
2000,
Pubmed Okamura,
Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity.
2000,
Pubmed Ponting,
PAS: a multifunctional domain family comes to light.
1997,
Pubmed Reppert,
Molecular analysis of mammalian circadian rhythms.
2001,
Pubmed Roth,
Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein.
1998,
Pubmed Saez,
Regulation of nuclear entry of the Drosophila clock proteins period and timeless.
1996,
Pubmed Sauman,
Circadian clock neurons in the silkmoth Antheraea pernyi: novel mechanisms of Period protein regulation.
1996,
Pubmed Sehgal,
Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation.
1995,
Pubmed Shearman,
Interacting molecular loops in the mammalian circadian clock.
2000,
Pubmed Shearman,
Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei.
1997,
Pubmed Shigeyoshi,
Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript.
1997,
Pubmed Takano,
Cloning and characterization of rat casein kinase 1epsilon.
2000,
Pubmed Takumi,
A light-independent oscillatory gene mPer3 in mouse SCN and OVLT.
1998,
Pubmed Ullman,
The nucleoporin nup153 plays a critical role in multiple types of nuclear export.
1999,
Pubmed
,
Xenbase Ullman,
Nuclear export receptors: from importin to exportin.
1997,
Pubmed Vielhaber,
Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon.
2000,
Pubmed Vielhaber,
Casein kinase I: from obscurity to center stage.
2001,
Pubmed Yagita,
Dimerization and nuclear entry of mPER proteins in mammalian cells.
2000,
Pubmed Zheng,
Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock.
2001,
Pubmed
