• 생명과학회지
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• 제27권10호
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• pp.1225-1231
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• 2017

암을 포함한 다양한 인간의 질병 발생이 circadian clock 유전자의 변형된 발현 양상과 깊은 연관관계를 나타내고 있다. 세포 주기와 세포 성장은 circadian rhythm과 연결되어 있으며, 이를 조절하는 clock 유전자의 비정상적인 발현은 결국 종양 발생과 암의 발달을 유발하게 된다. Circadian clock에 관한 분자적 기전은 다수의 clock activator와 clock repressor의 통합적인 조절에 따른 전사 및 번역이 포함된 음성피드백 고리로 구성되어 있다. 이러한 circadian rhythm의 자동조절 기전에 의해 전체 유전체의 약 10~15%가 전사 수준에서 영향받는 것으로 나타났다. 많은 clock 유전자들 중, Period 1 (Per1)과 Period 2 (Per2)는 clock repressor 유전자로 정상적인 생리적 리듬을 조절하는 것에 기여한다. PER1과 PER2는 cyclin, CDK, CKI를 포함하는 세포 주기 조절자의 발현에 관여함이 밝혀졌으며, 다양한 암에서 PER1과 PER2의 발현 감소가 보고되었다. 따라서, 본 논문에서는 PER1과 PER2의 circadian rhythm에서의 분자적 기능과 종양 발생과 관련된 PER1과 PER2의 하위 표적인자에 대해 살펴보고, 암 치료를 위한 새로운 치료 표적과 암의 예후를 예측하기 위한 분자 지표로써의 PER1과 PER2의 가능성에 대해 서술하고자 한다.

• Biomolecules & Therapeutics
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• 제26권4호
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• pp.358-367
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• 2018

Most organisms have adapted to a circadian rhythm that follows a roughly 24-hour cycle, which is modulated by both internal (clock-related genes) and external (environment) factors. In such organisms, the central nervous system (CNS) is influenced by the circadian rhythm of individual cells. Furthermore, the period circadian clock 2 (Per2) gene is an important component of the circadian clock, which modulates the circadian rhythm. Per2 is mainly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as other brain areas, including the midbrain and forebrain. This indicates that Per2 may affect various neurobiological activities such as sleeping, depression, and addiction. In this review, we focus on the neurobiological functions of Per2, which could help to better understand its roles in the CNS.

• 한국발생생물학회지:발생과생식
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• 제8권1호
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• pp.57-64
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• 2004

본 연구는 생쥐의 난소 및 정소 조직에서 발달 단계에 따라 나타나는 일주기성 clock유전자의 발현과 단백질의 발현 양상을 알아보고자 하였다. 생쥐의 난소 및 정소에서 일주기성 변화와 연관된 유전자(Period1(Per1), Period2(Per2), Period3(Per3), Cryptochromel(Cry1), Cryptochrome2 (Cry2), Clock, Bmall)와 시교차 상핵에서 분비되어 표적 조직 또는 기관으로 전달되는 물질로 알려진 Prokineticin (Prok2)에 대 한 수용체들 (Prok1r과 Prok2r), PERI 단백질의 발현 양상을 발달 단계에 따라 (post partum day; ppd 1, 7, 10, 21, 35) 확인하였다. 주요 clock 유전자들은 생후 발달 단계에 따라 각각 다양한 발현양상을 보였다. 난소의 경우 많은 난포가 성장을 시작하는 시기인 생후 7일과 10일을 전후하여 발현량이 대부분 증가하는 것을 볼 수 있었으며, 정소의 경우에도 발달 단계에 따라 7일에서 발현이 증가하는 양상을 보였다. 특히 clock유전자들은 생후 7일과 10일에서 상대적으로 높은 발현 양상을 보였다 시교차 상핵에서 분비되어 표적기관으로 분비되는 것으로 알려진 Prok2의 수용체의 경우에도 주요 주기성 유전자들의 발현이 증가하는 것과 같은 시기에 발현이 높아지는 것을 확인할 수 있었고, 생식소 발달 초기에 강하게 발현되나 차후 점진적으로 감소하는 것을 확인할 수 있었다. 또한 PER1의 발현양상을 면역조직화학적 방법으로 확인한 결과, 난포의 각 발달 단계에서 난소 내 정상적인 난포의 과립세포와 난자에서 높게 발현되는 것을 알 수 있었고, 상기의 결과는 Perl 유전자의 발현 양상과 일치함을 확인할 수 있었다 또한 정소 내 Per1 유전자와 PER1 단백질의 발현은 모두 생후 10일과 21일에서 감소하는 경향을 보이나 성적으로 성숙됨에 따라 다시 증가하는 것을 확인할 수 있어, PER1 단백질은 생식소의 발생 단계별로 다양한 발현 양상의 차이를 보이며, 정자와 난자의 정상적인 발달에 밀접한 연관이 있음을 추론할 수 있었다. 본 연구의 결과, 일주기성 clock유전자들 중 특히 Per1이 생식소의 정상 발달에 중요하게 작용할 수 있음을 시사하여 차후 이에 대한 다양한 연구가 진행되어야 할 것으로 생각된다.

• Animal cells and systems
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• 제16권1호
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• pp.27-33
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• 2012

The suprachiasmatic nucleus (SCN) of the teleost hypothalamus contains a central circadian pacemaker, which adjusts circadian rhythms within the body to environmental light-dark cycles. It has been shown that exposure to darkness during the day causes phase shifts in circadian rhythms. In this study, we examined the effect of exposure to darkness on the mRNA expression levels of two circadian clock genes, namely, $Period2$ ($Per2$) and $Cryptochrome1$ ($Cry1$), and the rate-limiting enzyme in melatonin synthesis, arylalkylamine $N$-acetyltransferase-2 (Aanat2), in the pineal gland of olive flounder, $Paralichthys$ $olivaceus$. The expression of these genes showed circadian variations and was significantly higher during the dark phase. These changes may be involved in the mechanism of dark-induced phase shifts. Furthermore, this study suggests that olive flounder may be a teleost model to investigate the localization and function of circadian oscillators.

• 대한의생명과학회지
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• 제12권1호
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• pp.53-56
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• 2006

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the circadian pacemaker entrained to the 24-hr day by environmental time cues. Major circadian genes such as mPeriod ($mPer1{\sim}3$) and mCryptochrome ($mCry1{\sim}2$) are actively transcribed by the action of CLOCK/BMAL heterodimers, and in turn, these are being suppressed by the mPER/mCRY complex. In the study, the locomotor activity rhythms of mPer1 Knockout (KO) mice are measured, and the expression profiles of Heat Shock Protein 105kDa (HSP 105) genes in the SCN were measured by in situ hybridization. In agreement with previous reports, the locomotor activity rhythm of mPer1 KO mice was much shorter than that of wildtype. In addition, the total bout of activity of mPer1 KO was less in comparison to control mice. The expression of HSP 105 in the SCN of mPer1 KO mice was ranged from CT6 to CT22, with a peak level at CT14, implying that the gene are under the control of circadian clock. However, the expression of HSP 105 in the SCN of wildtype could not be detected in our study. Further analysis will reveal the direct or indirect regulation by mPer1 on the expression in the SCN and the role of the gene in the circadian clock.

• Molecules and Cells
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• 제22권3호
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• pp.275-284
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• 2006

The molecular components that generate and maintain circadian rhythms of physiology and behavior in mammals are present both in the brain (suprachiasmatic nucleus; SCN) and in peripheral tissues. Examination of mice with targeted disruptions of either mPer1 or mPer2 has shown that these two genes have key roles in the SCN circadian clock. Here we show that loss of the clock gene mPer2 affects forced locomotor performance in mice without altering muscle contractility. A proteomic analysis revealed that the anterior tibialis muscles of the mPer2 knockout mice had higher levels of glycolytic enzymes such as triose phosphate isomerase and enolase than those of either the wild type or mPer1 knockout mice. In addition, the level of expression of HSP90 in the mPer2 mutant mice was also significantly higher than in wildtype mice. These results suggest that the reduced locomotor endurance of the mPer2 knockout mice reflects a greater dependence on anaerobic metabolism under stress conditions, and that the two canonical clock genes, mPer1 and mPer2, play distinct roles in the physiology of skeletal muscle.

• Reproductive and Developmental Biology
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• 제33권3호
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• pp.163-169
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• 2009

Many biological systems are regulated by an intricate set of feedback loops that oscillate with a circadian rhythm of roughly 24 h. This circadian clock mediates an increase in body temperature, heart rate, blood pressure, and cortisol secretion early in the day. Recent studies have shown changes in the amplitude of the circadian clock in the hearts and livers of streptozotocin (STZ)-treated rats. It is therefore important to examine the relationships between circadian clock genes and growth factors and their effects on diabetic phenomena in animal models as well as in human patients. In this study, we sought to determine whether diurnal variation in organ development and the regulation of metabolism, including growth and development during the juvenile period in rats, exists as a mechanism for anticipating and responding to the environment. Also, we examined the relationship between changes in growth factor expression in the liver and clock-controlled protein synthesis and turnover, which are important in cellular growth. Specifically, we assessed the expression patterns of several clock genes, including Per1, Per2, Clock, Bmal1, Cry1 and Cry2 and growth factors such as insulin-like growth factor (IGF)-1 and -2 and transforming growth factor (TGF)-${\beta}1$ in rats with STZ-induced diabetes. Growth factor and clock gene expression in the liver at 1 week post-induction was clearly increased compared to the level in control rats. In contrast, the expression patterns of the genes were similar to those observed after 5 weeks in the STZ-treated rats. The increase in gene expression is likely a compensatory change in response to the obstruction of insulin function during the initial phase of induction. However, as the period of induction was extended, the expression of the compensatory genes decreased to the control level. This is likely the result of decreased insulin secretion due to the destruction of beta cells in the pancreas by STZ.

• Molecules and Cells
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• 제43권3호
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• pp.276-285
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• 2020

Circadian rhythm is an endogenous oscillation of about 24-h period in many physiological processes and behaviors. This daily oscillation is maintained by the molecular clock machinery with transcriptional-translational feedback loops mediated by clock genes including Period2 (Per2) and Bmal1. Recently, it was revealed that gut microbiome exerts a significant impact on the circadian physiology and behavior of its host; however, the mechanism through which it regulates the molecular clock has remained elusive. 3-(4-hydroxyphenyl)propionic acid (4-OH-PPA) and 3-phenylpropionic acid (PPA) are major metabolites exclusively produced by Clostridium sporogenes and may function as unique chemical messengers communicating with its host. In the present study, we examined if two C. sporogenes-derived metabolites can modulate the oscillation of mammalian molecular clock. Interestingly, 4-OH-PPA and PPA increased the amplitude of both PER2 and Bmal1 oscillation in a dose-dependent manner following their administration immediately after the nadir or the peak of their rhythm. The phase of PER2 oscillation responded differently depending on the mode of administration of the metabolites. In addition, using an organotypic slice culture ex vivo, treatment with 4-OH-PPA increased the amplitude and lengthened the period of PER2 oscillation in the suprachiasmatic nucleus and other tissues. In summary, two C. sporogenes-derived metabolites are involved in the regulation of circadian oscillation of Per2 and Bmal1 clock genes in the host's peripheral and central clock machineries.

• 생명과학회지
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• 제25권11호
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• pp.1304-1310
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• 2015

주기성 시계 유전자 3(period circadian clock gene 3, PER3)는 포유류에서 생물학적 주기 타이밍 시스템의 역할을 수행 한다. 이 유전자는 규칙적인 운동 체계에 의해 근육에서 전사 개시 되는 것으로 알려져 있다. 인간과 마우스에서는 본 유전자에 대해 잘 알려져 있지만, 주기 및 연주기 동안 낮의 길이에 영향을 많이 받는 말에서 운동 연관 연구는 존재하지 않는다. 운동 시 근육의 기능에 중요한 역할을 하는 PER3 유전자에 대해 대표적인 경주마인 국내산 더러브렛 품종의 운동 전과 운동 후 유전자 발현을 분석하기 위해 본 연구를 수행하였다. 그 결과, 골격근에서 PER3 유전자의 발현은 운동 전에 비해 운동 후에 유의적으로 증가하는 것으로 나타났다. 또한, 인실리코상에서 4개의 비동의성 단일 염기 변이(non-synonymous single nucleotide polymorphism, nsSNP) 분석과 이러한 nsSNP의 단백질 구조 및 기능 분석 결과, 전체 자유 에너지와 RMSD 값은 돌연변이의 원인이 될 수 있음으로 나타났다. 이 중, nsSNP–s395916798 (G72R)은 구조적 기능적 측면에서 중요한 잔기의 안정화 효과와 연관된 것을 알 수 있었다. 본 연구는 운동에 따라 더러브렛 골격근 내 PER3 발현 차이는 운동이라는 표현형에 대표될 수 있음을 확인하였다. 또한, SNP의 조합을 활용하여 운동 후 경주마의 조기 회복의 평가 지표로써 유용한 바이오마커가 될 수 있음을 시사한다.

• 한국해양생명과학회지
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• 제9권1호
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• pp.47-52
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• 2024

Light is a major external environmental factor that influences the circadian rhythm of photosynthetic organisms and various physiological phenomena, such as growth, maturation, and behavior. The number of light-reaching organisms changes depending on the season and atmospheric conditions, and the intensity and wavelength of light differ depending on the organisms inhabiting the environment. Altered light changes the circadian rhythm of fish, which is controlled by clock genes, such as period 2 (Per2), cryptochrome 1 (Cry1), and melatonin. In this study, we set the zeitgeber time (ZT; 14 light-10 dark, LD) based on the actual sunrise and sunset times and examined Per2 and Cry1 activities, levels of aralkylamine N-acetyltransferase (AANAT), and melatonin in Pholis nebulosa, a drifting seaweed species exposed to irregular light. Per2 and Cry1 levels increased during the daytime and decreased after sunset. The AANAT levels decreased during the daytime and increased during the night. Melatonin concentration was highest around midnight (ZT21, 23:30), but exhibited similar concentrations during the daytime. While the activity of Per2, Cry1, and AANAT levels exhibited a typical circadian rhythm observed in most vertebrates, melatonin concentrations did not show a significant difference between the daytime and nighttime. These findings provide insights into the circadian rhythm patterns of organisms exposed to irregular light environments, such as P. nebulosa, which differ from those of typical fish species.