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SG1

G2 M

Physiological and therapeutic control exerted on:- transitions (checkpoints) between phases (G1/S, G2/M, M/G1)- death rates (apoptosis or necrosis) and progression speeds inside phases- exchanges between quiescent (G0) and proliferative phases (G1 only)

Mitotic human HeLa cell (from LBCMCP-Toulouse)

(from B. Basse et al., J Math Biol 2003)

di , Ki->i+1 constant or periodic w. r. to time t (1 i I, I+1=1)

ni:=cell population density in phase i ; vi :=progression speed; di:=death rate;

Ki-1->i:=transition rate (with a factor 2for i=1)

Flow cytometry

=CDK1 All cells in G1-S-G2 (phase i=1) All cells in M (phase i=2)

Entrainment of the cell division cycle by = CDK1 at the circadian period

time t

23 23 7 7 11

Arb

itrar

y un

its

Time (h)

NPV

Pineal

Lévi, Lancet Oncol 2001 ; Mormont & Lévi, Cancer 2003 (from Francis Lévi, INSERM U 776 Rythmes Biologiques et Cancers)

20 000 coupled neurons, in particular electrically (coupling blocked by TTX),each one of them oscillating according to a period ranging between 20 et 28 h…

…resulting in an endogenous periodicity of the central circadian oscillator, but with entrainment by light (through the retinohypothalamic tract) for VL neurons

Vs : Vs =1.6 (1+L cos(2 t/24)) target of entrainment by light L; K: target of transcriptional inhibition (e.g. by cytokines); Vm(i): the carrier of variabilility of the oscillatory period. 3 variables for the ith neuron that communicateswith all other (j i) neurons of the SCN throughcytosolic PER protein, with coupling constant Ke:electric? gap junctions? VIP / VPAC2 signalling?

(from Aton & Herzog, Neuron 2005)

(after Leloup, Gonze, Goldbeter, J Biol Rhythms 1999)

Desynchro D/D (T: varying around 21h30)

Desynchro D/D (T: varying around 21h30)

Synchro L/D (entrainment at T=24h)

Resulting Per to control Wee1, hence CDK1= , in proliferating cells

0 1 2 3 4 5 6 7

0

50

100

150

200

250

0 1 2 3 4 5 6 7

0

50

100

150

200

250

0 1 2 3 4 5 6 7

34

35

36

37

38

39

0 1 2 3 4 5 6 7

34

35

36

37

38

39

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Desynchro D/D (T: varying around 21h30)

Desynchro D/D (T: varying around 21h30)

Synchro L/D (entrainment at T=24h)

Resulting Per to control Wee1, hence CDK1= , in proliferating cells

Cyclin

P+

P

M+

X+ X

M

i d

1

2

3

4

cdc25

wee1

Cyclinprotease

Cdc2kinase

Mitotic oscillator model by Albert Goldbeter, 1997, here with circadian entrainment by a square wave standing for Wee1

(after U. Schibler,Science, Oct. 2003)

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