CHRONOBIOCHEMISTRY AND CARCINOGENESIS

By

SOMADE OLUWATOBI T. (B.Sc Biochemistry, M.Sc

in Cancer Research/Molecular Biology) University of
Ibadan, Ibadan Nigeria

Email address: toblerum@yahoo.co.uk

 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
 OVERVIEW

Fig 1: Some features of the human circadian

 INTRODUCTION
Chronobiochemistry is the branch of
biochemistry concerned with the biochemical
aspects of Chronobiology.

Chronobiology is the study of the inherent

rhythmicity or periodicity (biological clock) of
living organisms and their activities.
 INTRODUCTION
Living organisms evolved an internal
biological clock, called the Circadian rhythm,
to help their bodies adapt to the daily cycle of
day and night (light and dark) as the Earth
rotates every 24 hours.

The term 'circadian' comes from the Latin

phrase “circa diem” meaning “about a day”.
 INTRODUCTION

Circadian Rhythms and the Body.

Fig 2: Circadian RhythmsSource:Wager-Smith and Kay, 2000

 INTRODUCTION
This rhythm is generated by a molecular
clock that is present in virtually all cells in
humans and mice.

The peripheral clocks throughout the

organism are coordinated by a master clock
located in the suprachiasmatic nuclei (SCN) in
the hypothalamus.
 INTRODUCTION
Clock disruption by environmental or genetic
factors has been implicated in a number of
pathologic conditions.

Of interest, several epidemiologic studies and,

more recently, some studies with animal model
systems have suggested that circadian clock
disruption predisposes humans and mice to cancer.
Fig 3: HISTORICAL OVERVIEW OF CHRONOBIOLOGY
 

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

 THE CIRCADIAN CLOCK
The focal point of this system is a
master clock, located in the
suprachiasmatic nuclei (SCN) of the
anterior hypothalamus, which
orchestrates the circadian
programme.
THE CIRCADIAN CLOCK

Fig 4: Hierarchical organization of the circadian system.

(Reppert and Weaver 2002).

 THE CIRCADIAN CLOCK
 Under steady-state oscillating
conditions, the central clock is constantly
reset by environmental light cues and
generates circadian outputs in the
neuroendocrine and autonomic nervous
systems.
 Characteristic/Properties of Circadian
Rhythms/Cycle

 It has the ability to be synchronized or

entrained by external time cues such as the
light-dark cycle, temperature.

Ubiquity in nature.
 Determining the human circadian
rhythm
The classic phase markers for measuring the
timing of a mammal's circadian rhythm are:

Core body temperature.

Melatonin secretion by the pineal gland.

 How does light reset the biological
clock?
Only in recent years have scientists begun to
understand how the daily cycle of day and
night is transmitted from the eye to the master
clock in the brain.

Rhodopsin

Melanopsin
 Component Genes of the Mammalian
Circadian Clock
In the last few decades, scientists have discovered the
genes responsible for running the internal clocks:

Per (per1, per2, per 3),

Clock,
CK1ᵋ,
Cry (cry1, cry2),
Bmal
Cyc
 wc (wc-1, wc-2)

These genes are ubiquitous.

 THE CIRCADIAN CLOCK MECHANISM IN
MAMMALS

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

The disruption of circadian rhythms can result in health problems,

decreased alertness and poor sleep.

Exposure to light at night disturbs the circadian system with

alterations of the sleep/activity patterns, suppression of melatonin
production, and deregulation of circadian genes involved in cancer
related pathways.

Most of the studies that have analyzed the relationship between

nocturnal exposure to light (and shift work) and cancer have focused
on the role of melatonin.
 Melatonin
Three mechanisms have been suggested to
be involved in the apparent protective effects
against cancer of melatonin:

Light exposure during the night suppresses

nocturnal melatonin secretion, and does it in a
dose response manner: the brighter the light,
the greater the suppression.
 Melatonin
 The suprachiasmatic nucleus receives photic information via the
retinohypothalamic tract (RHT) and regulates melatonin secretion from
the pineal gland through a network of neurons.

The decrease in melatonin production has been suggested to induce an

increase in the levels of reproductive hormones such as estrogens, which
would then stimulate the growth and proliferation of hormone-sensitive
cells in the breast.

The potential role of melatonin as a protective agent against cancer is

reinforced by a series of studies evaluating the prevalence of breast
cancer among blind women who showed a decreased risk of developing
breast cancer.
 CIRCADIAN CYCLE AND CELL CYCLE

The circadian cycle and cell cycle are two

global regulatory mechanisms that directly or
indirectly influence all biochemical reactions
in cells.

Hence, it is logical to assume that disruption

of one would cause dysregulation of the other
with adverse consequences on the cell.
 CIRCADIAN CYCLE AND CELL CYCLE
Per2 mutant mice had constitutively elevated levels of
expression of the cell growth/proliferation gene c-Myc and
reduced expression of p53, which plays a critical role in the
G1-S checkpoint.

BMal1-Clock positively regulates Wee1, an anti-mitotic

kinase. BMal1-Clock also represses c-Myc transcription. The
transcription of c-Myc was reported to be highly elevated in
Per2 mutant mice. Per2 positively regulates BMal1
transcription and in the absence of Per2, the BMal1, a
repressor of c-Myc, is down) and the high incidence of IR
induced lymphoma in these mice was ascribed, at least in
part, to the elevated c-Myc.
 Circadian Clock and Cell Cycle Genes

P21
In Bmal1-null mice, a dramatic increase of
p21 mRNA levels was observed as compared
with wild type animals.

This observation suggests that BMAL1

represses p21 transcription.
 Circadian Clock and Cell Cycle Genes

p53

is expressed identically in Bmal1 mutant and wild type livers in which no significant
rhythmicity can be detected. p53 is therefore not controlled by the circadian clock genes.


Wee1

is a known clock target, regulating the G2/M transition. It is expressed at intermediate

and constant levels in Bmal1 animals.


The cell cycle inhibitor p21 gene and wee1 are circadian clock outputs and these two
genes are differentially affected by the Bmal1 mutation.

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

 
 Circadian Clock and Cell Cycle Genes

Bmal1-Clock

Fig 7: Molecular links between circadian clock and cell cycle genes.
Source: Gery et al. 2006
 CIRCADIAN CYCLE GENES AND CANCER

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 recently demonstrated
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 their

neoplastic growth and increases their apoptotic rate. In vivo studies
showed that mice deficient in mPer2 showed significant higher
incidences of tumor development after genotoxic stress.
 CIRCADIAN CYCLE GENES AND CANCER

Recent studies demonstrate that both PER1

and PER2 are involved in DNA damage
response pathways and implicate normal
circadian function as a factor in tumor
suppression.
 CONCLUSION
Disruptions to rhythms usually have negative effects.

 Lack of synchrony within the internal environment might lead to

health problems in the individual, such as those associated with jet lag,
shift work, and the accompanying sleep loss (e.g., impaired cognitive
function, altered hormonal function, and gastrointestinal complaints).

 Disruption to rhythms in the longer term is believed to have

significant adverse health consequences on peripheral organs outside
the brain.

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

The suppression of melatonin production associated with the

disruption of the circadian rhythm may increase the risk of developing
cancer .