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fisher1

fisher1

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R1

Calcineurin dpdnt NFAT dephosphorylation

Act_C_Nuc + NFAT_Pi_Nuc = NFAT_Nuc + Act_C_Nuc

R10

Phosphorylated NFAT transport

NFAT_Pi_Cyt = NFAT_Pi_Nuc

R11

NFAT Calcineurin complex disassembly

NFAT_Act_C_Cyt = NFAT_Cyt + Act_C_Cyt

R12

Calcineurin dpdnt NFAT dephosphorylation

Act_C_Cyt + NFAT_Pi_Cyt = NFAT_Cyt + Act_C_Cyt

R13

Calcineurin activation

Inact_C_Cyt + {3.0}Ca_Cyt = Act_C_Cyt

R14

Calcineurin activation

Inact_C_Nuc + {3.0}Ca_Nuc = Act_C_Nuc

R15

Inactive Calcineurin transport

Inact_C_Cyt = Inact_C_Nuc

R16

Calcium transport

Ca_Cyt = Ca_Nuc

R17

Phosphorylated NFAT Calcineurin complex transport

NFAT_Pi_Act_C_Cyt = NFAT_Pi_Act_C_Nuc

R2

NFAT Calcineurin complex formation

NFAT_Nuc + Act_C_Nuc = NFAT_Act_C_Nuc

R3

NFAT transport

NFAT_Nuc = NFAT_Cyt

R4

Active Calcineurin transport

Act_C_Nuc = Act_C_Cyt

R5

NFAT Calcineurin complex phosphorylation

NFAT_Act_C_Nuc = NFAT_Pi_Act_C_Nuc

R6

Phosphorylated NFAT Calcineurin complex disassembly

NFAT_Pi_Act_C_Nuc = NFAT_Pi_Nuc + Act_C_Nuc

R7

NFAT Calcineurin complex transport

NFAT_Act_C_Nuc = NFAT_Act_C_Cyt

R8

NFAT Calcineurin complex phosphorylation

NFAT_Act_C_Cyt = NFAT_Pi_Act_C_Cyt

R9

Phosphorylated NFAT Calcineurin complex disassembly

NFAT_Pi_Act_C_Cyt = NFAT_Pi_Cyt + Act_C_Cyt

Parameters

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Fixed species

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Events

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


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NFAT and NFkappaB activation in T lymphocytes: a model of differential activation of gene expression.

  • Wayne G Fisher
  • Pei-Chi Yang
  • Ram K Medikonduri
  • M Saleet Jafri
Ann Biomed Eng 2006; 34 (11): 1712-1728
Abstract
Mathematical models for the regulation of the Ca(2+)-dependent transcription factors NFAT and NFkappaB that are involved in the activation of the immune and inflammatory responses in T lymphocytes have been developed. These pathways are important targets for drugs, which act as powerful immunosuppressants by suppressing activation of NFAT and NFkappaB in T cells. The models simulate activation and deactivation over physiological concentrations of Ca(2+), diacyl glycerol (DAG), and PKCtheta using single and periodic step increases. The model suggests the following: (1) the activation NFAT does not occur at low frequencies as NFAT requires calcineurin activated by Ca(2+) to remain dephosphorylated and in the nucleus; (2) NFkappaB is activated at lower Ca(2+) oscillation frequencies than NFAT as IkappaB is degraded in response to elevations in Ca(2+) allowing free NFkappaB to translocate into the nucleus; and (3) the degradation of IkappaB is essential for efficient translocation of NFkappaB to the nucleus. Through sensitivity analysis, the model also suggests that the largest controlling factor for NFAT activation is the dissociation/reassociation rate of the NFAT:calcineurin complex and the translocation rate of the complex into the nucleus and for NFkappaB is the degradation/resynthesis rate of IkappaB and the import rate of IkappaB into the nucleus.

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