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5th
EMBL/EMBO Joint Conference 2004 |
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Session I |
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| The
time measuring systems of cells and organisms |
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Many biochemical and
physiological processes fluctuate in a temporal
fashion. Cycles with a period length [t] of approximately
24 hours are considered to be circadian, while rhythms
with substantially shorter and longer period lengths
are called ultradian and infradian, respectively.
Virtually all light-sensitive organisms –
from cyanobacteria to humans – contain circadian
oscillators, and in mammals most vital processes
are subject to circadian variations. Thus sleep-wake
cycles, locomotor activity, heartbeat, blood pressure,
renal plasma flow, body temperature, sensorial perception,
and the secretion of many hormones fluctuate during
the day in an orderly fashion. The mammalian master
circadian pacemaker resides in the suprachiasmatic
nucleus [SCN] at the base of the brainŠs hypothalamus.
The phase of this SCN clock is reset every day via
the retino-hypothalamic tract, which transmits light
information from the retina directly to SCN neurons.
Circadian pacemakers were originally believed to
exist only in a few specialized cell types, such
as SCN neurons. However, in recent years, this view
has been challenged by the discovery that circadian
clocks exist in most peripheral cell types, even
in immortalized tissue culture cells. As feeding
time is the major Zeitgeber for peripheral clock,
the SCN may synchronize peripheral oscillators mostly
by driving rest-activity cycles, which in turn determine
feeding time. On the molecular level, circadian
oscillations are generated by interconnected eedback
loops in gene expression, involving the transcriptional
repressors CRY1, CRY2, PER1, PER2, and REV-ERBa,
the transcriptional activators CLOCK and BMAL1,
and several protein kinases [e.g. protein kinase
1e]. The molecular clock drives the cyclic accumulation
and/or activity of downstream regulators, which
in turn govern the rhythmic expression of enzymes
and thus circadian physiology. One family of such
downstream regulators will be discussed in detail. |
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