Question

Explain how the apoptotic pathway can be activated when TNF binds to its receptor? Name and explain any relevant proteins.

Name a cancer specific pathway drug/treatment and explain its mechanism.  

Answer 1

TNF-a is tumour necrosis factor.It a cytokine involved in immunity an inflammation.The TNF cytokine binds to its receptor called TNFR1.Binding of TNF-a to TNFR1 causes receptor trimerization and a conformation change. This allows for the binding and docking of death domain adaptor proteins. Apoptosis is triggered by death inducing signalling complex which contains FADD and caspase-8.The apoptosis inhibition pathway is NF-kB dependent, and inhibition of NF-kB markedly increases apoptotic response to TNF-a.This switch depends on intracellular concentration of cell signalling intermediates.

            

Binding of TNF-a to TNFR1 leads to the recruitment of the death domain proteins TRADD, TRAF2, and RIP-1 to the

ligand-receptor complex. These proteins form the multi-protein complex called the early complex which is required for the downstream activities.

Caspases are central in activating the apoptotic machinery.

Caspases are generally divided into two categories—

initiator caspases and effector caspases. The early complex (c9) when bound to FADD and then procaspase-8, leads to activation of the apoptotic signaling machinery via the DISC, c21.DISC releases active caspase-8 which is now capable of activating the effector, caspase-3.

Inhibition of NF-kB may lead to a therapeutic approach in fighting a disease like cancer.