Table 3 Reactions involved in p53 turnover and the DNA damage response

25

p53 synthesis

p53_mRNA→p53+p53_mRNA

k_synp53 <#p53_mRNA>

7.0E-3 s^-1

26

p53 Mdm2 binding

p53+Mdm2 → Mdm2_p53

k_binMdm2p53<#p53><#Mdm2>

3.0E-3 molecule^-1 s^-1

27

Mdm2_p53 release

Mdm2_p53→p53+Mdm2

k_relMdm2p53 <#Mdm2_p53>

3.0E-5 s^-1

E1/Ub binding

E1+Ub+ATP→E1_Ub+AMP

k_binE1Ub<#E1><#Ub><#ATP>/(5000 +<#ATP>)

2.0E-4 molecule^-1 s^-1

E2/Ub binding

E1_Ub+E2→E2_Ub+E1

k_binE2Ub<#E2><#E1_Ub>

1.0E-3 molecule^-1 s^-1

28

p53 ubiquitination

Mdm2_p53+E2_Ub→Mdm2_p53_Ub+E2

k_p53Ub<#Mdm2_p53><#E2_Ub>

5.0E-5 molecule^-1 s^-1

29

p53 polyubiquitination1

Mdm2_p53_Ub+E2_Ub→Mdm2_p53_

Ub2+E2

k_p53PolyUb<#Mdm2_p53_Ub><#E2_Ub>

1.0E-2 molecule^-1 s^-1

30

p53 polyubiquitinationX

(X = 2-3)

Mdm2_p53_Ub(X)+E2_Ub→

Mdm2_p53_Ub(X+1)+E2

k_p53PolyUb<#Mdm2_p53_Ub(X)><#E2_Ub>

1.0E-2 molecule^-1 s^-1

p53 de-ubiquitination1

Mdm2_p53_Ub+p53DUB →

Mdm2_p53+p53DUB+Ub

k_actDUBp53<#Mdm2_p53_Ub>

<#p53DUB>

1.0E-7 molecule^-1 s^-1

p53 de-ubiquitinationX

(X = 2-4)

Mdm2_p53_Ub(X)+p53DUB →

Mdm2_p53_Ub(X-1)+p53DUB+Ub

k_actDUBp53<#Mdm2_p53_Ub(X)>

<#p53DUB>

1.0E-7 molecule^-1 s^-1

31

p53 Proteasome binding

Mdm2_P_p53_Ub4+Proteasome→

p53_Ub4_Proteasome+Mdm2

k _binProt <# Mdm2_P_p53_Ub4><#Proteasome>

2.0E-6 molecule^-1 s^-1

32

p53 degradation

p53_Ub4_Proteasome+ATP→

4Ub+Proteasome+ADP

k_degp53<#p53_Ub4_Proteasome> <#ATP>/(5000 + <#ATP>)

1.0E-2 s^-1

33

Mdm2mRNA synthesis1

p53→p53+Mdm2_mRNA

k_synMdm2mRNA<#p53>

5.0E-4 s^-1

(33)

Mdm2mRNA synthesis2

p53_P→p53_P+Mdm2_mRNA

k_synMdm2mRNA<#p53_P>

5.0E-4 s^-1

34

Mdm2 mRNA degradation

Mdm2_mRNA→Sink

k_degMdm2mRNA<#Mdm2_mRNA>

5.0E-4 s^-1

35

Mdm2 synthesis

Mdm2_mRNA→Mdm2_mRNA+Mdm2

k_synMdm2<#Mdm2_mRNA>

4.95E-4 s^-1

Mdm2 ubiquitination^b

Mdm2+E2_Ub→Mdm2_Ub+E2

k_Mdm2Ub<#Mdm2><#E2_Ub>

4.56E-6 molecule^-1 s^-1

Mdm2 polyubiquitination1^c

Mdm2_Ub+E2_Ub→Mdm2_Ub2+E2

k_Mdm2PolyUb<#Mdm2_Ub><#E2_Ub>

4.56E-3 molecule^-1 s^-1

Mdm2 polyubiquitinationX^c

(X = 2-3)

Mdm2_Ub(X)+E2_Ub→Mdm2_Ub(X+1)+E2

k_Mdm2PolyUb<#Mdm2_Ub(X)><#E2_Ub>

4.56E-3 molecule^-1 s^-1

Mdm2 de-ubiquitination1^c

Mdm2_Ub+Mdm2DUB →

Mdm2+Mdm2DUB+Ub

k_actDUBMdm2<#Mdm2_Ub><#Mdm2DUB>

1.0E-7 molecule^-1 s^-1

Mdm2 de-ubiquitinationX^c

(X = 2-4)

Mdm2_Ub(X)+Mdm2DUB →

Mdm2_Ub(X-1)+Mdm2DUB+Ub

k_actDUBMdm2<#Mdm2_Ub(X)>

<#Mdm2DUB>

1.0E-7 molecule^-1 s^-1

Mdm2 proteasome binding^c

Mdm2_Ub4 + Proteasome→Mdm2_Ub4_Proteasome

k _binProt <# Mdm2_Ub4><#Proteasome>

2.0E-6 molecule^-1 s^-1

Mdm2 degradation^c

Mdm2_Ub4_Proteasome+ATP→

4Ub+Proteasome+ADP

k_degMdm2<#Mdm2_Ub4_Proteasome>

<#ATP>/(5000+<#ATP>)

1.0E-2 molecule^-1 s^-1

36

ATM activation

damDNA+ATMI→damDNA+ATMA

k _actATM <#damDNA><#ATMI>

1.0E-4 molecule^-1 s^-1

37

ATM inactivation

ATMA → ATMI

k _inactATM <#ATMA>

5.0E-4 s^-1

38

p53 phosphorylation

p53+ATMA→p53_P+ATMA

k_phosp53<#p53><#ATMA>

2.0E-4 molecule^-1 s^-1

39

p53 dephosphorylation

p53_P→p53

k_dephosp53<#p53_P>

5.0E-1 s^-1

Mdm2 phosphorylation

Mdm2+ATMA→Mdm2_P+ATMA

k_phosMdm2<#Mdm2><#ATMA>

2.0 molecule^-1 s^-1

Mdm2 de-phosphorylation

Mdm2_P→Mdm2

k_dephosMdm2<#Mdm2_P>

5.0E-1 s^-1

40

p53mRNA synthesis

Source→p53_mRNA

k _synp53mRNA

1.0E-3 molecule s^-1

41

p53mRNA degradation

p53_mRNA→Sink

k_degp53mRNA<#p53_mRNA>

1.0E-4 s^-1

42

DNA damage by IR

IR→damDNA+ IR

k _dam <#IR>

8.0E-2 s^-1

43

DNA repair

damDNA→Sink

k _repair <#damDNA>

2.0E-5 s^-1

44

DNA damage by ROS

ROS→damDNA+ROS

k _damROS <#ROS>

1.0E-5 s^-1

(44)

DNA damage by basalROS

basalROS→damDNA+ basalROS

k _dambasalROS <#basalROS>

1.0E-9 s^-1