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Table 2 Logical rules associated with the regulatory network of Fig 1 and interpretation of the multi-levels.

From: Modelling the onset of senescence at the G1/S cell cycle checkpoint

Node

Rule / level interpretation

ATM

1: DSB = 1

Low level of DSB signal

 

2: DSB = 2

High level of DSB signal

ATR

1: SSB = 1

Low level of SSB signal

 

2: SSB = 2

High level of SSB signal

CHEK2

1: ATM = 2

CHEK1

1: ATR = 2 OR ATM = 2

p14ARF

1: p38MAPK = 2 OR E2F

p38MAPK

1: (ATM = 1 OR ATR = 1-2) AND NOT(ATM = 2)

Activated p38MAPK pathway (leading to cycle arrest)

 

2: ATM = 2 AND NOT(ATR = 2)

Middle level of p38MAPK pathway activation (leading to senescence)

 

3: ATM = 2 AND ATR = 2

Highest level of p38MAPK pathway activation (leading to apoptosis)

Mdm2

1: p53 = 1 AND NOT(p14ARF)

p16INK4A

1: p38MAPK = 1-2

Activated p16INK4A

 

2: p38MAPK = 3

p16 INK4A upregulation

p21

1: p53 = 1

p53

1: Mdm2 = 1 AND (p38MAPK = 3 OR ATR = 1-2 OR ATM = 1-2 OR CHEK1 = 1 OR CHEK2 = 1)

Activated p53 (no accumulation)

 

2: NOT(Mdm2 = 1) AND (p38MAPK = 3 OR ATR = 1-2 OR ATM = 1-2 OR CHEK1 = 1 OR CHEK2 = 1)

p53 accumulation leading to apoptosis

CDC25A

1: (p38MAPK = 1-3 OR CHEK2 = 1 OR CHEK1 = 1) AND NOT(p38MAPK = 1-3 AND CHEK2 = 1 AND CHEK1 = 1)

Low concentration of active Cdc25A (i.e. non-phosphorylated)

 

2: NOT(p38MAPK = 1-3) AND NOT(CHEK2 = 1) AND NOT(CHEK1 = 1)

High concentration of active Cdc25A

E2F

1: NOT(RB1 = 1)

RB1

1: NOT(CDK46CycDc = 1) AND NOT(CDK2CycEc =1)

Dephosphorylated RB1 bound to E2F

CDK46CycD

1: Cdc25A = 1 AND NOT(p16INK4a = 1-2) AND NOT(p21 = 1)

CDK2CycE

1: NOT(p21 = 1) AND Cdc25A = 2 AND E2F = 1

apoptosis

1: p53 = 2

proliferation

1: CDK2CycEc = 1

senescence

1: (p16INK4a = 1 AND p21 = 1 AND NOT(Cdc25A = 1-2) AND NOT(p53 = 2)) OR (p16INK4a = 2 AND p21 = 1 AND NOT(Cdc25A = 2) AND NOT(p53 = 2))

cyclearrest

1: NOT(CDK2CycEc = 1)

  1. Input components (DSB and SSB) are constant and thus do not appear in this table. Rules are defined using the logical connectors AND, OR and NOT. For each node, they specify its target value, depending on the state of its regulators. Note that 0 is the default value (selected whenever none of the conditions defined for other values are verified).