CHRONOBIOCHEMISTRY & CARCINOGENESIS

8/7/2019 CHRONOBIOCHEMISTRY & CARCINOGENESIS

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CHRONOBIOCHEMISTRY AND

CARCINOGENESISBy

SOMADE OLUWATOBI T. (B.Sc Biochemistry,M.Sc in Cancer Research/Molecular Biology)

University of Ibadan, Ibadan Nigeria

Email address: [email protected]


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OUTLINES

INTRODUCTION

HISTORY OF CHRONOBIOLOGY

THE CIRCADIAN CLOCK

CHARACTERISTIC PROPERTIES OF THE CIRCADIAN RHYTHM

DETERMINING THE HUMAN CIRCADIAN RHYTHM

HOW DOES LIGHT RESET THE BIOLOGICAL CLOCK?

COMPONENT GENES OF THE MAMMALIAN CIRCADIAN CLOCK

CIRCADIAN CLOCK MECHANISM IN MAMMALS

SHIFT WORK AND CANCER

MELATONIN

CIRCADIAN CYCLE AND CELL CYCLE

CIRCADIAN CYCLE AND CELL CYCLE GENES

CIRCADIAN CYCLE GENES AND CANCER

CONCLUSION


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Fig 1: Some features of the human circadian

OVERVIEW


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INTRODUCTIONChronobiochemistry is the branch of

biochemistry concerned with the biochemicalaspects of Chronobiology.

Chronobiology is the study of the inherentrhythmicity or periodicity (biological clock) of

living organisms and their activities.


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INTRODUCTIONLiving organisms evolved an internal

biological clock, called the Circadian rhythm,to help their bodies adapt to the daily cycle ofday and night (light and dark) as the Earthrotates every 24 hours.

The term 'circadian' comes from the Latinphrase circa diem meaning about a day.


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INTRODUCTION

Circadian Rhythms and the Body.

Fig 2: Circadian Rhythms Source:Wager-Smith and Kay, 2000


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INTRODUCTION

This rhythm is generated by a molecularclock that is present in virtually all cells inhumans and mice.

The peripheral clocks throughout theorganism are coordinated by a master clock

located in the suprachiasmatic nuclei (SCN) inthe hypothalamus.


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INTRODUCTIONClock disruption by environmental or genetic

factors has been implicated in a number ofpathologic conditions.

Of interest, several epidemiologic studies and,more recently, some studies with animal modelsystems have suggested that circadian clockdisruption predisposes humans and mice to cancer.


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Fig 3: HISTORICAL OVERVIEW OF CHRONOBIOLOGY

Source: Lee J. Siegel, with additional contributions by Stephanie Watson.


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THE CIRCADIAN CLOCK

The focal point of this system is amaster clock, located in the

suprachiasmatic nuclei (SCN) of theanterior hypothalamus, whichorchestrates the circadianprogramme.


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THE CIRCADIAN CLOCK

Fig 4: Hierarchical organization of the circadian system.

(Reppert and Weaver 2002).


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THE CIRCADIAN CLOCK

Under steady-state oscillating conditions, the central clock is constantlyreset by environmental light cues and

generates circadian outputs in theneuroendocrine and autonomic nervoussystems.


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Characteristic/Properties of CircadianRhythms/Cycle

It has the ability to be synchronized orentrained by external time cues such as thelight-dark cycle, temperature.

Ubiquity in nature.


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Determining the human circadianrhythm

The classic phase markers for measuring thetiming of a mammal's circadian rhythm are:

Core body temperature.

Melatonin secretion by the pineal gland.


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How does light reset the biologicalclock?

Only in recent years have scientists begun tounderstand how the daily cycle of day andnight is transmitted from the eye to the masterclock in the brain.

Rhodopsin

Melanopsin


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Component Genes of the MammalianCircadian Clock

In the last few decades, scientists have discovered thegenes responsible for running the internal clocks:

Per ( per1, per2, per 3 ),

Clock ,CK 1 ,Cry ( c ry1, c ry2),Bma l

Cycwc (wc-1 , wc-2 )

These genes are ubiquitous.


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THE CIRCADIAN CLOCK MECHANISM INMAMMALS

Fig 6: The molecular mechanism of the biological clock. Source: [King et al. 1997; Darlington et al. 1998; Gekakis et al. 1998; Jin et al. 1999].


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Shift work could increase cancer risk

When exposure occurs at a time when the body would normally

not be exposed to light, that is, at night, the circadian rhythm isdisrupted.

The disruption of circadian rhythms can result in healthproblems, decreased alertness and poor sleep.

Exposure to light at night disturbs the circadian system withalterations of the sleep/activity patterns, suppression of melatoninproduction, and deregulation of circadian genes involved in cancerrelated pathways.

Most of the studies that have analyzed the relationship betweennocturnal exposure to light (and shift work) and cancer havefocused on the role of melatonin.


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Melatonin

Three mechanisms have been suggested tobe involved in the apparent protective effectsagainst cancer of melatonin:

Light exposure during the night suppresses

nocturnal melatonin secretion, and does it in adose response manner: the brighter the light,the greater the suppression.


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MelatoninThe suprachiasmatic nucleus receives photic information via the

retinohypothalamic tract (RHT) and regulates melatonin secretionfrom the pineal gland through a network of neurons.

The decrease in melatonin production has been suggested toinduce an increase in the levels of reproductive hormones such asestrogens, which would then stimulate the growth andproliferation of hormone-sensitive cells in the breast.

The potential role of melatonin as a protective agent againstcancer is reinforced by a series of studies evaluating the prevalenceof breast cancer among blind women who showed a decreased riskof developing breast cancer.


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CIRCADIAN CYCLE AND CELL CYCLE

The circadian cycle and cell cycle are twoglobal regulatory mechanisms that directly orindirectly influence all biochemical reactions

in cells.

Hence, it is logical to assume that disruption

of one would cause dysregulation of the otherwith adverse consequences on the cell.


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CIRCADIAN CYCLE AND CELL CYCLEPer2 mutant mice had constitutively elevated levels of

expression of the cell growth/proliferation gene c-Myc andreduced expression of p53, which plays a critical role in theG1-S checkpoint.

BMal1-Clock positively regulates Wee1, an anti-mitotickinase. BMal1-Clock also represses c-M yc transcription. Thetranscription of c-M yc was reported to be highly elevated in P er2 mutant mice. Per2 positively regulates BMal1

transcription and in the absence of Per2, the BMal1, arepressor of c-M yc , is down) and the high incidence of IRinduced lymphoma in these mice was ascribed, at least inpart, to the elevated c-Myc.


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Circadian Clock and Cell Cycle Genes

P21

In Bma l 1-null mice, a dramatic increase of

p21 mRNA levels was observed as comparedwith wild type animals.

This observation suggests that BMAL1represses p21 transcription.


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p53

is expressed identically in Bmal1 mutant and wild type livers in which nosignificant rhythmicity can be detected. p53 is therefore not controlled bythe circadian clock genes.

W ee1

is a known clock target, regulating the G2/M transition. It is expressed atintermediate and constant levels in Bma l 1 animals.

The cell cycle inhibitor p21 gene and wee1 are circadian clock outputsand these two genes are differentially affected by the Bma l 1 mutation.

Therefore p21, Wee1, and c-Myc are clock-controlled genes.


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Fig 7: Mol ecul a r l in ks b etwee n c ir c ad ia n clock a nd cell c ycl e g enes.Sou r ce: Gery et a l. 2006

Bmal1-Clock


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Loss and dysregulation of Per1 and Per2 gene expression have

been found in many types of human cancers.

The significance of proper circadian regulation to cell cycle

progression and the DNA damage response was recentlydemonstrated by studies in Cry and Per2 mutant mice, showing improper cell division and increased sensitivity to radiation.

Overexpression of either Per1 or Per2 in cancer cells inhibits theirneoplastic growth and increases their apoptotic rate. In vivo studiesshowed that mice deficient in mPer2 showed significant higherincidences of tumor development after genotoxic stress.


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Recent studies demonstrate that both PER1and PER2 are involved in DNA damage

response pathways and implicate normalcircadian function as a factor in tumorsuppression.


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CONCLUSIONDisruptions to rhythms usually have negative effects.

Lack of synchrony within the internal environment might lead tohealth problems in the individual, such as those associated with jetlag, shift work, and the accompanying sleep loss (e.g., impairedcognitive function, altered hormonal function, and gastrointestinalcomplaints).

Disruption to rhythms in the longer term is believed to havesignificant adverse health consequences on peripheral organsoutside the brain.

Mutations and disruption in circadian clock genes alter the cellcycle functions, thus, adverse consequences on the cell.

The suppression of melatonin production associated with thedisruption of the circadian rhythm may increase the risk ofdeveloping cancer .

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CHRONOBIOCHEMISTRY & CARCINOGENESIS