Molecular Medicine Israel

Cell Death and Differentiation (2011); Doi: 10.1038/cdd.2011.131.
Sandow, J.J., Jabbour, A.M., Condina, M.R., Daunt, C.P.,  Stomski, F.C., Green, B.D., Riffkin, C.D., Hoffmann, P., Guthridge, M.A., Silke, J., Lopez, A.F. & Ekert, P.G.
“Cytokine receptor signaling activates an IKK-dependent phosphorylation of
PUMA to prevent cell death”.

Cells can recover from the brink of disaster by selectively eliminating a protein that commits them to a program of self-destruction.

Cytokine proteins transmit essential biological instructions, and many cells will commit ‘suicide’ via a process known as apoptosis following a prolonged absence of these signals. This mechanism is triggered by increased production of PUMA, a protein that broadly inhibits the various cellular factors that normally prevent apoptosis.

However, some cells retain the capacity to bounce back from the brink of self-destruction. Research from a team led by Australian researchers Angel Lopez of the Centre for Cancer Biology and Paul Ekert of the Walter and Eliza Hall Institute for Medical Research now reveals how PUMA’s deadly effects may be countered following the restoration of cytokine signals.

The researchers found that PUMA is chemically modified by a phosphate group in cells stimulated with the cytokine interleukin-3 after a period of cytokine depletion. They also found that this modification targets that protein for rapid destruction. When the gene encoding PUMA was mutated to introduce an amino acid substitution at this modification site, the protein became considerably more stable.

Lopez, Ekert and colleagues were subsequently able to focus on a well-known enzymatic complex that coordinates and catalyzes PUMA phosphorylation in response to restored cytokine signaling. They hypothesize that this may represent a critical rescue pathway that prevents cells from ‘overreacting’ to temporary crises.


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