Kohn’s first map formalization within K0


Preliminary notes :

Binding to regulatory regions is treated just as binding of proteins so
that these pieces of DNA are treated syntactically as proteins.

In fact rules could be asked to respect the following invariant:

- for each A, at most one #A in the solution.

- for each C, at most one # in C.

But assuming that we have a descriptive formalism it’s not necessary to
include this in the data model because we just have to write proper rules.

The same we use in data set a contextual notation to reduce both  the
number of rules to write and the number of reaction we need to describe
extensively (less redundancy).

The idea is to give a triplet (rule : A,B->A’*B’, A context, B context).
A, B are proteins or complexes and their context precise if the rule is
still valid when A (Resp. B) are bound to other complexes (context: list
of such partner)

Note: this include various orders of formation for a same complex (a
same tricomplex can have 2 different ways of binding visible in context.
As our formalism is associative the resulting tricomplex is the same).
Around 200 rules with theses contexts .

 

Data Model Hypotheses (fit to Kohn formalization):

- Descriptive

- Associative and commutative complexation.

- No domain

- No contextual rules

- No location

- No transport events

- Equivalent notation : _

- implicit inhibition; no “non reaction”.

 

Data Set Hypotheses :

- No cyclic complex

- Independent contexts

- No decomplexation : see pRb as regards to its  internal state.

- Internal state are precised when it’s necessary. Eventually
unnecessary rules may be written (e.g. phosphorylation of cdk1 when in
complex with cycA while this phosphorylation was necessary for the binding).

- By default activation of a protein hold for corresponding complex.

- By default independent binding are competitive (and not
concurrent/simultaneous).

- There is no order for promoter element binding: proteins bind
themselves and finally the super complex binds the promoter (after no
more protein can bind). This hypothesis is really biologically wrong but
there is a lack of information in the map around regulation and it’s a
shortcoming before understanding (see alternative notation for E2
promoter regulation): we have to read all annotations and references.

- Total inhibition: as for skp2 (others seem false or partial: C23)

- Context: if A.B is in C context this mean that A.B.C exists
but perhaps A.B doesn’t exist.

- Alternative notations: Raf1, synthesis
(cycA<>|cycE<y>|cycD<z>|c-Myc<>|p19ARF<>|p107<t>|Pol<> because of lack
of information), undetailed supercomplex(primase).

- synthesis: we don’t precise the internal state.

- Kohn shows only useful phosphorylations sites.

- Wrong information: more than one skp2, p21.. (C27)

- correspondence with Kohn annotation are more or less given.


Protein list (69) of the Cyclin-E2F cell cycle control: 

SL1<x>

CycH<>

Cdk7<x>

PCNA<>

RPA<>

p68<x,y>

Pol<>

Skp1<x>

p53<x>

Mdm2<>

c-Myc<>

AP2<>

Max<>

E-cadherin<>

pCAF<>

p300<>

histones<x>

HDAC1<>

p16<>

p21<>

p27<x>

p57<>

cycD<x>

cycE<x>

cycA<>

cycB<>

cdk4/6<x,y>

cdk2<x,y>

cdk1<x,y,z>

cdc25A<x>

cdc25C<x,y>

DMP1<x>

Gadd45<>

Skp2<x>

Chk1<>

C-TAK1<>

Cks1<>

APC<x>

Plk1<>

Wee1<x>

Myt1<

14-3-3<>

Ras<>

Raf1<>

p19ARF<>

c-Abl<>

pRb<x,y>

p107<x>

p130<x>

E2F1-3<x>

E2F4<>

E2F5<>

E2F6<>

DP1/2<x>

Sp1<>

HBP1<>

Jun<>

c-Fos<>

ERCC1<>

C/EBP<>

#p19ARF

#ERCC1

#E2/SP

#P

P<X>

#E-cadherin

#cdc25A

#E2

 

 

 

 

 

 

 


Cyclin-CDK Box

 

 

    * Cdk binding to a Cyclin

 

(C3) cdk4/6<x,y>={cdk4<x,y>,cdk6<x,y>} (global)

 

« To begin with, cdk activity requires binding to a cyclin »

 

(C3,C10) (cdk4/6<x,y>|cycD<z>->cdk4/6.cycD<x,y;z>; {}; {DMP1<t>})

 

%cycA and cycE compete in binding cdk2%

(C4,C6) (cdk2<x,y>|cycA<>->cdk2.cycA<x,y;>; {Cks1<>}; {})

(C4,C6) (cdk2<x,y>|cycE<z>->cdk2.cycE<x,y;z>; {Cks1<>}; {})

 

%cycA and cycB compete in binding cdk1%

(C5,C6,C14) (cdk1<x,y,1>|cycA<>->cdk1.cycA<x,y,1;>; {Cks1<>}; {})

(C5,C6) (cdk1<x,y,z>|cycB<>->cdk1.cycB<x,y,z;>; {Cks1<>}; {})

 

(cdk7<x>|cycH<>->cdk7.cycH<x;>; {}; {})

 

    * Cdk stimulatory (and inhibitory) phosphorylations

 

« All Cdks are activated by a phosphorylation carried out by cycH.cdk7 »

(C14) (cdk7.cycH<0;>[cdk7<0>->cdk7<1>]; {}; {cycH<>})

(C14,C6) (cdk7.cycH<0;>[cdk1<x,y,0>->cdk1<x,y,1>]; {}; {Cks1<>, cycA<>,
cycB<>, Cks1.cycA<;>, Cks1.cycB<;>})

(C14,C6) (cdk7.cycH<0;>[cdk2 <x,0>->cdk2<x,1>]; {}; {Cks1<>, cycA<>,
cycE<y>, cycA.E2F1-3<;y>, Cks1.cycA<;>, Cks1.cycE<;y>,
Cks1.cycA.E2F1-3<;;y>})

(C14) (cdk7.cycH<0;>[cdk4/6<x,0>->cdk4/6<x,1>]; {}; {cycD<y>,
cycD.DMP1<y;z>})

 

« inhibitory phosphorylations »

(C16) (Wee1<0>[cdk1.cycA <x,0,y;>->cdk1.cycA<x,1,y;>]; {}; {Cks1<>})

(C16) (Wee1<0>[cdk1.cycB <x,0,y;>->cdk1.cycB<x,1,y;>]; {}; {Cks1<>})

(C16) (Myt1<>[cdk1.cycA <0,x,y;>->cdk1.cycA <1,x,y;>]; {}; {Cks1<>})

(C16) (Myt1<>[cdk1.cycB <0,x,y;>->cdk1.cycB <1,x,y;>]; {}; {Cks1<>})

(C16) (Wee1<0>[cdk2.cycA <0,x;>->cdk2.cycA <1,x;>]; {}; {Cks1<>, E2F1-3<y>})

(C16) (Wee1<0>[cdk2.cycE <0,x;y>->cdk2.cycE<1,x;y>]; {}; {Cks1<>})

 

« positive feedback : cdc25C remove inhibitory phosphorylations»

(C18) (cdc25C<1,z>[cdk1<x,1,y>->cdk1<x,0,y>]; {}; {Cks1<>, cycA<>,
cycB<>, Cks1.cycA<;>, Cks1.cycB<;>})

(C18) (cdc25C<1,z>[cdk1<1,x,y>->cdk1<0,x,y>]; {}; {Cks1<>, cycA<>,
cycB<>, Cks1.cycA<;>, Cks1.cycB<;>})

 

    * Cdc25C and CDC25A phosphorylations

 

(C37) (Plk1<>[cdc25C<0,x>->cdc25C<1,x>]; {}; {})

 

« positive feedback »

(C36) (cdk1.cycA<0,0,1;>[cdc25C<0,x>->cdc25C<1,x>]; {Cks1<>}; {})

(C36) (cdk1.cycB<0,0,1;>[cdc25C<0,x>->cdc25C<1,x>]; {Cks1<>}; {})

 

« cdc25C sequestered »


  (C38) (Chk1<>[cdc25C<x,0>->cdc25C<x,1>]; {}; {})

(C39) (C-TAK1<>[cdc25C<x,0>->cdc25C<x,1>]; {}; {})__

(C40) (14-3-3<>|cdc25C<x,1>->14-3-3.cdc25C<;x,1>; {}; {})

 

« RAS activation : alternative notation needed to represent a
complicated process that we can’t (don’t want) explain. »

(C24) (Ras<>|Raf1<>[cdc25A<0>->cdc25A<1>]; {}; {})

(E22) (Ras<>[Raf1<>|cdc25A<x>->Raf1.cdc25A<;x>]; {}; {})

 

«cdc25A  phosphorylations»

(cdc25A<1>[cdk4/6<1,x>->cdk4/6<0,x>]; {}; {cycD<y>, cycD.DMP1<y;z>})

(cdc25A<1>[cdk2<1,x>->cdk2<0,x>]; {}; {Cks1<>, cycA<>, cycE<y>,
cycA.E2F1-3<;y>, Cks1.cycA<;>, Cks1.cycE<;y>, Cks1.cycA.E2F1-3<;;y>})

 

 

    * Other cyc.cdk phosphorylations

 

« internal regulation »

(C42) (cdk1.cycA<0,0,1;>[Wee1<0>->Wee1<1>]; {Cks1<>}; {})

(C42) (cdk1.cycB<0,0,1;>[Wee1<0>->Wee1<1>]; {Cks1<>}; {})

 

(C28) (cdk2.cycA<0,1;>[Skp2<0>->Skp2<1>]; {Cks1<>}; {Skp1<x>,
Skp1.cdk2.cycA<x;y,z;>, Skp1.cdk2.Cks1.cycA<x;y,z;;>})

(C27) (cdk2.cycA<0,1;>[Skp1<0>->Skp1<1>]; {Cks1<>}; {Skp2<x>,
Skp2.cdk2.cycA<x;y,z;>, Skp2.cdk2.Cks1.cycA<x;y,z;;>})

(C27) (cdk2.cycA<0,1;>[p68<x,0>->p68<x,1>]; {Cks1<>}; {})

 

(cdk2.cycE<0,1;x>[cycE<0>->cycE<1>]; {Cks1<>}; {cdk2 <y,z>,
cdk2.Cks1<y,z;>})

(R2) (cdk2.cycE<0,1;x>[p68<0,y>->p68<1,y>]; {Cks1<>}; {})

 

(C42) (cdk4/6.cycD<0,1;x>[DMP1<0>->DMP1<1>] ; {DMP1<y>}; {})

 

« Transcription »

(C42) (cdk1.cycA<0,0,1>[SL1<0>->SL1<1>]; {Cks1<>}; {})

(C42) (cdk1.cycB<0,0,1>[SL1<0>->SL1<1>]; {Cks1<>}; {})

 

« E2F Box »

(E20) (cdk2.cycA.E2F1-3<0,1;;x>[E2F1-3<0>->E2F1-3<1>]; {Cks1<>}; {Sp1<>})

(E20) (cdk2.cycA.E2F1-3<0,1;;x>[DP1/2<0>->DP1/2<1>]; {Cks1<>}; {p53<y>})

 

(C31) (cdk4/6.cycD<0,1;x>[pRb<0,y>->pRb<1,y>]; {DMP1<z>}; {})

(C32) (cdk2.cycE<0,1;x>[pRb<1,0>->pRb<1,1>]; {Cks1<>}; {})

%pRb can’t be in a complex if hyperphosphorylated. Thus there is no context%

 

    * Implicit inhibition

 

(C43) (p16<>|cdk7<x>->p16.cdk7<;x>; {}; {})

(C8) (p16<>|cdk4/6<x,y>->p16.cdk4/6<;x,y>; {}; {})*/__/*

* *

(C23,R6) (PCNA<>|p21<>->PCNA.p21<;>; {}; {cdk2.cycA<x,y;>,
cdk2.Cks1.cycA<x,y;;>})

 

(C23) (p21<>|cdk2.cycA<x,y;>->p21.cdk2.cycA <;x,y;>; {PCNA<>}; {Cks1<>})

(C23) (p21<>|cdk2.cycE<x,y;z>-> p21.cdk2.cycE<;x,y;z>; {}; {Cks1<>})

(C7) (p21<>|cdk4/6.cycD<x,y;z>->p21.cdk4/6.cycD<;x,y;z>; {}; {DMP1<t>})

(C23) (p27<>|cdk2.cycA<x,y;>-> p27.cdk2.cycA <;x,y;>; {}; {Cks1<>})

(C23) (p27<>|cdk2.cycE<x,y;z>-> p27.cdk2.cycE<;x,y;z>; {}; {Cks1<>})

(C7) (p27<>|cdk4/6.cycD<x,y;z>->p27.cdk4/6.cycD<;x,y;z>; {}; {DMP1<t>})

(C23) (p57<>|cdk2.cycA<x,y;>-> p57.cdk2.cycA <;x,y;>; {}; {Cks1<>})

(C23) (p57<>|cdk2.cycE<x,y;z>-> p57.cdk2.cycE<;x,y;z>; {}; {Cks1<>})

(C7) (p57<>|cdk4/6.cycD<x,y;z>->p57.cdk4/6.cycD<;x,y;z>; {}; {DMP1<t>})

 

« p19Skp1 et p45SKp2 »

 

(C26) (Skp1<x>|Skp2<y>->Skp1.Skp2<x;y>; {}; {cdk2.cycA<z,t;>,
cdk2.Cks1.cycA<z,t;;>})

 

(C25) (Skp2<x>|cdk2.cycA<y,z;>->Skp2.cdk2.cycA<x;y,z;>; {Skp1<t>}; {Cks1<>})

 

    * Degradation

 

(C9) (cycD<1>->; {}; {})

%alternative notation : degradation + unbinding%

(S9) (cdk4/6.cycD<x,y;1>->cdk4/6<x,y>; {}; {})

 

(C13) (cycE<1>->; {}; {})

 

%This paradoxical relationship might be due to intermolecular action of
an active cdk2.cycE on an inactive p27.cdk2.cycE%

(C21) (cdk2.cycE<0,1;x>[p27<0>->p27<1>]; {Cks1<>}; {cdk2.cycE<y,z;t>})

(C21) (p27<1>->; {}; {})

 

(C29) (Skp2.Skp1<x;y>[cycA<>-> ]; {}; {})**

 

(C41) (Plk1<>[APC<0>->APC<1>]; {}; {})

(C41) (APC<1>[cycB<>-> ]; {}; {})

 

    * Miscellaneous

 

« Cks1 may be involved in the dephophorylation of cdk Tyr15 »

 

(C6) (cdk1<x,y,z>|Cks1<>->cdk1.Cks1<x,y,z;>; {cycA<>, cycB<>}; {})

(C6) (cdk2<x,y>|Cks1<>->cdk2.Cks1<x,y;>; {cycA<>, cycA.E2F1-3<;z>,
cycE<z>}; {})

 

(C10) (DMP1<x>|cycD<y>->DMP1.cycD<x;y>; {}; {cdk4/6<z,t>})

 

(C11) (DMP1<x>|#p19ARF->DMP1<x>.#p19ARF; {}; {})

(C11) (DMP1<1>.#p19ARF+[->p19ARF<>]; {}; {})

 

    * Replication

 

(R11) (PCNA<>|cycD<x>->PCNA.cycD<;x>; {}; {})

(R10) (PCNA<>|Gadd45<>->PCNA.Gadd45<;>; {}; {})

(C34) (p21<>|Gadd45<>->p21.Gadd45<;>; {}; {})

(C30) (cdk1<x,y,z>|Gadd45<>->cdk1.Gadd45<x,y,z;>; {Cks1<>}; {})

%Gadd45 binds cdk1 and inhibits cdk1 activity%

(S9) (RPA<>|cycA<>->RPA.cycA<;>; {}; {})

 

    * P53 box

 

 

%more detail in 6b%

(Mdm2<>|E2F1-3.DP1/2<x;y>->Mdm2.E2F1-3.pRb<;x;y>; {}; {})

(Mdm2<>|pRb<x,y>->Mdm2.pRb<;x,y>; {}; {})

 

(p53<x>+[->Mdm2<>]; {}; {})

(P43) (p53<x>+[->p21<>]; {}; {})

(P44) (p53<x>+[->Gadd45<>]; {}; {})

(P48) (p53<x>+[->c-Fos<>]; {}; {})


E2F box

 

E2F1-3<x>={E2F1<x>,E2F2<x>,E2F3<x>} (global)

 

    * E2F.DP1/2

 

(E1) (E2F1-3<0>|DP1/2<0>->E2F1-3.DP1/2<0;0>; {SP1<>}; {})

(E1) (E2F4<>|DP1/2<0>->E2F4.DP1/2<;0>; {}; {})

(E1) (E2F5<>|DP1/2<0>->E2F5.DP1/2<;0>; {}; {})

(E1) (E2F6<>|DP1/2<0>->E2F6.DP1/2<;0>; {}; {})

 

(P26) (p53<x>|DP1/2<y>->p53.DP1/2<x;y>; {}; {})

 

    * E2F.DP1/2 binding

 

(E2) (pRb<z,0>|E2F1-3.DP1/2<x;y>->pRb.E2F1-3.DP1/2<z,0;x;y>; {c-Abl<>,
c-Abl.Raf1<;>, Raf1<>}; {SP1<>})

 

(E3) (p130<0>|E2F4.DP1/2<;x>->p130.E2F4.DP1/2<0;;x>; {Raf1<>}; {})

(E3) (p107<0>|E2F4.DP1/2<;x>->p107.E2F4.DP1/2<0;;x>; {Sp1<>}; {})

(E3) (pRb<z,0>|E2F4.DP1/2<;x>->pRb.E2F4.DP1/2<z,0;;x>; {c-Abl<>,
c-Abl.Raf1<;>, Raf1<>}; {})

 

(E4) (p130<0>|E2F5.DP1/2<;x>->p130.E2F5.DP1/2<0;;x>; {Raf1<>}; {})

(HBP1<>|p130<0>->HBP1<>.p130<;0>; {}; {Raf1<>})

 

    * E2F.DP1/2 synthesis

 

(E5) (E2F1-3.DP1/2<x;0>|#E2->E2F1-3.DP1/2<x;0>.#E2; {pRb<y,z>,
c-Abl.pRb<;y,z>, c-Abl.pRb.Raf1<;y,z;>, Raf1.pRb<;y,z>, SP1<>,
pRb.SP1<y,z;>, c-Abl.pRb.SP1<;y,z;>, c-Abl.pRb.Raf1.SP1<;y,z;;>,
Raf1.pRb.SP1<;y,z;>}; {})

 

(E6)
(E2F1-3.DP1/2<x;y>.#E2+[->cycA<>|cycE<z>|cycD<t>|c-Myc<>|p19ARF<>|p107<u>|Pol<>];
{}; {})

(E7)
(pRb.E2F1-3.DP1/2<x,y;z;t>.#E2-[->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>];
{c-Abl<>, SP1<>, c-Abl.SP1<;>}; {})

 

(E22)
(Raf1.pRb.E2F1-3.DP1/2<;x,y;z;t>.#E2+[->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>];
{c-Abl<>, SP1<>, c-Abl.SP1<;>}; {})

 

(E13)
(HDAC1<>|pRb.E2F1-3.DP1/2<x,y;z;t>->HDAC1.pRb.E2F1-3.DP1/2<;x,y;z;t>;
{}; {c-Abl<>, SP1<>, c-Abl.SP1<;>})

(E7) (HDAC1.pRb.E2F1-3.DP1/2<;x,y;;z;t>|#E2->
HDAC1.pRb.E2F1-3.DP1/2<;x,y;z;0>.#E2; {c-Abl<>, SP1<>, c-Abl.SP1<;>}; {})

(E14) (HDAC1.pRb.E2F1-3.DP1/2<;x,y;z;t>.#E2--[
->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>]; {c-Abl<>,
SP1<>, c-Abl.SP1<;>}; {})

 

(E5) (E2F4.DP1/2<;0>|#E2-> E2F4.DP1/2<;0>.#E2; {pRb<x,y>,
c-Abl.pRb<;x,y>, c-Abl.pRb.Raf1<;x,y;>, Raf1.pRb<;x,y>, p130<x>,
Raf1.p130<;x>, p107<x>, SP1.p107<;x>} ; {})

 

(E6)
(E2F4.DP1/2<;x>.#E2+[->cycA<>|cycE<y>|cycD<z>|c-Myc<>|p19ARF<>|p107<t>|Pol<>];
{}; {})

 

(E7)
(pRb.E2F4.DP1/2<x,y;;z>.#E2-[->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>];
{c-Abl<>}; {})

 

(E22)
(Raf1.pRb.E2F4.DP1/2<;x,y;;z>.#E2+[->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>];
{c-Abl<>}; {})

 

(E7)
(p130.E2F4.DP1/2<;;x>.#E2-[->cycA<>|cycE<y>|cycD<z>|c-Myc<>|p19ARF<>|p107<t>|Pol<>];
{}; {})

 

(E22)
(Raf1.p130.E2F4.DP1/2<;x;;y>.#E2+[->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>];
{}; {})

 

(E7)
(p107.E2F4.DP1/2<x;;y>.#E2-[->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>];
{SP1<>}; {})

 

(E13) (HDAC1<>|pRb.E2F4.DP1/2<x,y;;z>->HDAC1.pRb.E2F4.DP1/2<;x,y;;z>;
{}; {c-Abl<>})

(E7) (HDAC1.pRb.E2F4.DP1/2<;x,y;;z>|#E2->
HDAC1.pRb.E2F4.DP1/2<;x,y;;z>.#E2; {c-Abl<>}; {})

(E14) (HDAC1.pRb.E2F4.DP1/2<;x,y;;z>.#E2--[
->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>]; {c-Abl<>}; {})

 

(E13) (HDAC1<>| p130.E2F4.DP1/2<x;;y>->HDAC1.p130.E2F4.DP1/2<;x;;y>; {}; {})

(E7) (HDAC1.p130.E2F4.DP1/2<;x;;y>|#E2->
HDAC1.p130.E2F4.DP1/2<;x;;y>.#E2; {}; {})

(E14) (HDAC1.p130.E2F4.DP1/2<;x;;y>.#E2 --[
->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>]; {}; {})

 

(E13) (HDAC1<>|p107.E2F4.DP1/2<x;;y>->HDAC1.p107.E2F4.DP1/2<;x;;y>; {};
{SP1<>})

(E7) (HDAC1.p107.E2F4.DP1/2<;x;;y>|#E2->
HDAC1.p107.E2F4.DP1/2<;x;;y>.#E2; {SP1<>}; {})

(E14) (HDAC1.p107.E2F4.DP1/2<;x;;y>.#E2 --[
->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>]; {SP1<>}; {})

 

(E5) (E2F5.DP1/2<;0>|#E2-> E2F5.DP1/2<;0>.#E2; {p130<x>, Raf1.p130<;x>}; {})

 

(E6)
(E2F5.DP1/2<;x>.#E2+[->cycA<>|cycE<y>|cycD<z>|c-Myc<>|p19ARF<>|p107<t>|Pol<>];
{}; {})

 

(E7)
(p130.E2F5.DP1/2<x;;y>.#E2-[->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>];
{}; {})

 

(E22)
(Raf1.p130.E2F5.DP1/2<;x;y>.#E2+[->cycA<>|cycE<y>|cycD<z>|c-Myc<>|p19ARF<>|p107<t>|Pol<>];
{}; {})

 

(E13) (HDAC1<>| p130.E2F5.DP1/2<x;;y>->HDAC1.p130.E2F5.DP1/2<;x;;y>; {}; {})

(E7) (HDAC1.p130.E2F5.DP1/2<;x;;y>|#E2->
HDAC1.p130.E2F5.DP1/2<;x;;y>.#E2; {}; {})

(E14)
(HDAC1.p130.E2F5.DP1/2<;x;;y>.#E2--[->cycA<>|cycE<u>|cycD<v>|c-Myc<>|p19ARF<>|p107<w>|Pol<>];
{}; {})

 

(E8) (E2F6.DP1/2<;x>|#E2->E2F6.DP1/2<;x>.#E2; {}; {})

(E9) (E2F6.DP1/2<;x>.#E2-[
->cycA<>|cycE<y>|cycD<z>|c-Myc<>|p19ARF<>|p107<t>|Pol<>]; {}; {})

 

    * Synthesis modulation

 

 « Sp1 »

(E24) (SP1<>|E2F1-3<x>->SP1.E2F1-3<;x>; {}; {DP1/2<y>, pRb.DP1/2<z,t;y>,
c-Abl.pRb.DP1/2<;z,t;y >, c-Abl.pRb.Raf1.DP1/2<;z,t;;y >,
Raf1.pRb.DP1/2<;z,t;y>})

(E26) (SP1<>|p107<x>->SP1.p107<;x>; {}; {E2F4.DP1/2< y;>})

(E20) (cdk2.cycA<x,y;>|E2F1-3<z>->cdk2.cycA.E2F1-3<x,y;z>; {Cks1<>}; {})

 

(E23) (SP1<>|#E2/SP->SP1<>.#E2/SP; {E2F1-3<x>, E2F1-3.DP1/2<x;y>,
pRb.E2F1-3.DP1/2<x,y;z;t >, c-Abl.pRb.E2F1-3.DP1/2<;x,y;z;t>,
c-Abl.pRb.Raf1.E2F1-3.DP1/2<;x,y;;z;t>,
Raf1.pRb.E2F1-3.DP1/2<;x,y;z;t>}; {})

 

% (E27) binding of p107 to Sp1 seems to inhibit the binding of Sp1 to DNA%

*/_ _/*

(E23)
(SP1<>.#E2/SP+[->cycA<>|cycE<y>|cycD<z>|c-Myc<>|p19ARF<>|p107<t>|Pol<>];
{}; {})

(E25)
(SP1.E2F1-3<;x>.#E2/SP++[->cycA<>|cycE<y>|cycD<z>|c-Myc<>|p19ARF<>|p107<t>|Pol<>];
{DP1/2<y>, pRb.DP1/2<x,y;z;t >, c-Abl.pRb.DP1/2<;y,z;t>,
c-Abl.pRb.Raf1.DP1/2<;y,z;;t>, Raf1.pRb. DP1/2<;y,z;t>}; {})

 

/«Raf : alternative notation»/

 (E22) (Ras<>[Raf1<>|pRb<x,0>->Raf1.pRb<;x,0>]; {}; {c-Abl<>,
E2F4.DP1/2<;y>, c-Abl.E2F4.DP1/2<;;y >,  E2F1-3.DP1/2<y;z>,
c-Abl.E2F1-3.DP1/2<;y;z >, SP1.E2F1-3.DP1/2<;y;z >,
c-Abl.SP1.E2F1-3.DP1/2<;;y;z >})

/(E22) (Ras<>[Raf1<>|p130<x>->Raf1.p130<;x>]; {}; {E2F5.DP1/2<;y>,
E2F4.DP1/2< ;y>, HBP1<>})/

 

    * Chromatin & acetylase box

 

(pCAF<>|p300<>->PCAF.p300<;>; {}; {})

(pCAF<>[histones<0>->histones<1>]; {}; {})

(p300<>[histones<0>->histones<1>]; {}; {})

(H1) (HDAC1<>[histones<1>->histones<0>]; {}; {})

 

(H1)
(histones<0>-[->cycA<>|cycE<x>|cycD<y>|c-Myc<>|p19ARF<>|p107<z>|Pol<>];
{}; {})

 

    * Other pRB interactions

 

(E18) (c-Abl<>|pRb<x,y>->c-Abl.pRb<;x,y>; {}; {Raf1<>, E2F4.DP1/2<;z>,
Raf1.E2F4.DP1/2<;;z >, E2F1-3.DP1/2<z;t >, Raf1.E2F1-3.DP1/2<;z;t>,
SP1.E2F1-3.DP1/2<;;z;t>, Raf1.SP1.E2F1-3.DP1/2<;;z;t>})

(E17) (pRb<x,y>|Jun<>->pRb.Jun<x,y;>; {}; {c-Fos<>})

(E16) (C/EBP<>|pRb<x,y>->C/EBP.pRb<;x,y>; {}; {})

 

(E17) (Jun<>|c-Fos<>->Jun.c-Fos<;>; {pRb<x,y>}; {})

(E17) (Jun.c-Fos<;>|#ERCC1->Jun.c-Fos<;>.#ERCC1; {pRb<x,y>}; {})

(E17) (Jun.c-Fos<;>.#ERCC1+[->ERCC1<>]; {}; {})

 

(E17) (pRb.Jun.c-Fos<x,y;;>.#ERCC1++[->ERCC1<>]; {}; {})

 

(E16) /(C/EBP<>|#P->C/EBP<>.#P/; {pRb<x,y>}; {})//

(E16) /(C/EBP<>.#P+[->P<X>]/; {}; {})*//*

*/ /*

(E16) /(C/EBP.pRb<;x,y>.#P++[->P<X>]/; {}; {})//

*/ /*

    * Myc box

 

(M2) (c-Myc<>|Max<>->c-Myc.Max<;>; {}; {})

(C35) (c-Myc.Max<;>|#cdc25A->c-Myc.Max<;>.#cdc25A; {}; {})

(C35) (c-Myc.Max<;>.#cdc25A+[->cdc25A<x>]; {}; {})

 

(M1) (c-Myc<>|AP2<>->c-Myc.AP2<;>; {}; {})

(M1) (pRb<x,y>|AP2<>->pRb.AP2<x,y;>; {}; {})

 

(M3,4) (AP2<;>|#E-cadherin->AP2<;>.#E-c; {c-Myc<>, pRb<x,y>}; {})

(M3) (AP2<;>.#E-cadherin+[->E-cadherin<>]; {}; {})*//*

(M4) (pRb.AP2<x,y;>.#E-cadherin++[->E-cadherin<>]; {}; {})

(M4) (c-Myc.AP2<;>.#E-cadherin++[->E-cadherin<>]; {}; {})

 

    * Degradation

 

(P130<1>->; {}; {})

(E10) (E2F4<>->; {}; {})

(E10) (p130.E2F4.DP1/2<x;;y>-[E2F4<>->]; {}; {})

%unbinding + degradation needed%

 

 


Additional informations :

 

Competitive binding (same site):

({p16<>,cycD<x>}, {cdk4/6<y,z>})

({p21<>,p27<x>,p57<>}, {cdk4/6.cycD<x,y ;z>,cdk2.cycE< x,y ;z
>,cdk2.cycA< x,y ;>})

({p21<>,Gadd45<>},{PCNA<>} )

({cycE<x>, cycA<>},{cdk2<y,z>})

({cycA<>, cycB<>,Gadd45<>},{cdk1<x,y,z>})

({cdk1<x,y,z>, cdk2<x,y>},{Cks1<>})

({cdk2.cycA<x,y ;>,Sp1<>},{E2F1-3})

({E2F1-3<x>, E2F4<>, E2F5<>, E2F6<>,p53<x>},{DP1/2})

({E2F1-3.DP1/2<x;y>, E2F4.DP1/2< ;x>},{pRb<z,t>})

({E2F4.DP1/2< ;x>, E2F5.DP1/2< ;x>,HBP1<>},{p130<z>})

({Jun<>,C/EBP<>},{pRb<x,y>})

({pRb<x,y>,c-Myc<>},{AP2<>})

({E2F1-3.DP1/2<x;y>, E2F4.DP1/2<;x>, E2F5.DP1/2<;x>, E2F6.DP1/2<;x>},{#E2})

 

Concurrent binding:

({Cks1<>,cycA<>, cycB<>},{cdk1<x,y,z>})

({Cks1<>,cycA<>, cycE<>},{cdk2<x,y>})

({DMP1<>,cdk4/6<x,y>},{cycD<z>})

({CycA.cdk2<;x,y>,PCNA<>},{p21<>})

({CycA.cdk2<;x,y >,skp1<z>},{skp2<t>})

({Raf1<>, c-Abl<>, E2F1-3.DP1/2<u;v>, E2F4.DP1/2<;v>},{pRb<x,y>})

({Raf1<>, E2F5.DP1/2<;v>, E2F4.DP1/2<;v>},{p130<x>})

({Sp1<>, pRb<x,y>},{ E2F1-3.DP1/2<u;v>})

({Sp1<>, E2F1-3.DP1/2<u;v>},{p107<x>})