Systems Biology (Methods in Molecular Biology)

Here, Cyclin D-CDK4/6 means the concentration or activity of
this protein. f(E2F, Myc, C/EBPα, p21, GSK‐ 3 β) means the
integrated production rate of CyclinD-CDK4, CyclinDτcyclinD‐‐CDK4CDK4= 6 =^6
means the degradation term of CyclinD-CDK4/6, τcyclin D‐

CDK4/6 was the degradation constant of protein Cyclin
D-CDK4/6. We further assume that the activation of CyclinD-
CDK4/6 needs activated E2F or Myc, and at the same time inacti-
vated C/EBPα, p21, and GSK-3β. Then, the integrated production
rate of CyclinD-CDK4/6,f(E2F, Myc, C/EBPα, p21, GSK‐ 3 β),
is quantified in Eq.2:

fðÞE2F;Myc;C=EBPα;p21;GSK‐ 3 β

¼VcyclinD‐CDK4= 6 

½ŠE2F

K 11

n 11

þ ½ŠMycK 12

n 12

1 þ ½ŠE2FK 11

n 11

þ ½ŠMycK 12

n 12



1

1 þ ½ŠC=KEBP 13 α

n 13

þ ½ŠKp21 14

n 14

þ ½ŠGSkK 15 ‐^3 β

n 15

ð 2 Þ

VcyclinD‐CDK4/6means the maximal production rates of pro-
tein CyclinD-CDk4,n 1 iand K 1 iare parameters of biochemical
reaction, which is used to describe the detailed weight of each
protein in regulating the production of Cyclin D-CDK4.

It is impossible to obtain all the parameters, fortunately as we
focus on the relative concentration or activity of these agents, we
can grasp the key features of the interactions and architecture by
assuming appropriate parameter values. In this framework, the
content or activity of each protein was normalized to range from
0 to 1, 0 means minimal content or activity, 1 means maximal. The
maximal production rate,VcyclinD‐CDK4/6, and the degradation
rate,τcyclinD‐CDK4/6, may be normalized as 1. We assume thatn 1 i
¼3 andK 1 i¼8 to grasp the key feature of activation or inhibi-
tion, we have validated that the values ofn 1 iandK 1 ican be relaxed
without affecting the conclusions we made in this paper [49]. With
these assumptions, the equation may be simplified in Eq.3:

d CyclinD½Š‐CDk4= 6

dt

¼

8 ½ŠE2F^3 þ 8 ½ŠMyc^3

1 þ 8 ½ŠE2F^3 þ 8 ½ŠMyc^3



1

1 þ 8 ½ŠC=EBPα^3 þ 8 ½Šp21^3 þ 8 ½ŠGSK‐ 3 β^3

½ŠCyclinD‐CDK4= 6

ð 3 Þ

The quantitative assumptions provide a general framework to
quantify endogenous network, the function types and parameters
can be relaxed without affecting the major conclusions. It seems

Endogenous Molecular-Cellular Network Cancer Theory 223