InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: PER1

Summary

InnateDB Protein

IDBP-28000.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

PER1

Protein Name

period homolog 1 (Drosophila)

Synonyms

hPER; PER; RIGUI;

Species

Homo sapiens

Ensembl Protein

ENSP00000314420

InnateDB Gene

IDBG-27996 (PER1)

Protein Structure

UniProt Annotation

Function

Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time- keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCKNPAS2-ARNTL/BMAL1ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1, NR1D2, RORA, RORB and RORG, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. Regulates circadian target genes expression at post-transcriptional levels, but may not be required for the repression at transcriptional level. Controls PER2 protein decay. Represses CRY2 preventing its repression on CLOCK/ARNTL target genes such as FXYD5 and SCNN1A in kidney and PPARA in liver. Besides its involvement in the maintenance of the circadian clock, has an important function in the regulation of several processes. Participates in the repression of glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) by ARNTL:CLOCK. Plays a role in the modulation of the neuroinflammatory state via the regulation of inflammatory mediators release, such as CCL2 and IL6. In spinal astrocytes, negatively regulates the MAPK14/p38 and MAPK8/JNK MAPK cascades as well as the subsequent activation of NFkappaB. Coordinately regulates the expression of multiple genes that are involved in the regulation of renal sodium reabsorption. Can act as gene expression activator in a gene and tissue specific manner, in kidney enhances WNK1 and SLC12A3 expression in collaboration with CLOCK. Modulates hair follicle cycling. Represses the CLOCK- ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. {ECO:0000269PubMed:24005054}.

Subcellular Localization

Nucleus. Cytoplasm. Note=Nucleocytoplasmic shuttling is effected by interaction with other circadian core oscillator proteins and/or by phosphorylation. Retention of PER1 in the cytoplasm occurs through PER1-PER2 heterodimer formation. Translocate to the nucleus after phosphorylation by CSNK1D or CSNK1E. Also translocated to the nucleus by CRY1 or CRY2 (By similarity). {ECO:0000250}.

Disease Associations

Tissue Specificity

Widely expressed. Expressed in hair follicles (at protein level).Found in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, kidney, spleen, thymus, prostate, testis, ovary and small intestine. Highest level in skeletal muscle. {ECO:0000269PubMed:14750904, ECO:0000269PubMed:24005054, ECO:0000269PubMed:9333243, ECO:0000269PubMed:9427249}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 30 experimentally validated interaction(s) in this database.
They are also associated with 24 interaction(s) predicted by orthology.

Experimentally validated
Total	30 [view]
Protein-Protein	24 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	4 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	24 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000976	transcription regulatory region sequence-specific DNA binding
GO:0000978	RNA polymerase II core promoter proximal region sequence-specific DNA binding
GO:0000989	transcription factor binding transcription factor activity
GO:0004871	signal transducer activity
GO:0005515	protein binding
GO:0008134	transcription factor binding
GO:0019900	kinase binding
GO:0031490	chromatin DNA binding
GO:0031625	ubiquitin protein ligase binding
GO:0070888	E-box binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0002028	regulation of sodium ion transport
GO:0006351	transcription, DNA-templated
GO:0007165	signal transduction
GO:0007623	circadian rhythm
GO:0009416	response to light stimulus
GO:0009649	entrainment of circadian clock
GO:0010608	posttranscriptional regulation of gene expression
GO:0032922	circadian regulation of gene expression
GO:0042634	regulation of hair cycle
GO:0042752	regulation of circadian rhythm
GO:0043124	negative regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043153	entrainment of circadian clock by photoperiod
GO:0043966	histone H3 acetylation
GO:0043967	histone H4 acetylation
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0046329	negative regulation of JNK cascade
GO:0070932	histone H3 deacetylation
GO:0097167	circadian regulation of translation
GO:1900015	regulation of cytokine production involved in inflammatory response
GO:1900744	regulation of p38MAPK cascade
GO:2000323	negative regulation of glucocorticoid receptor signaling pathway