- Survival of the fittest clone: Pro-apoptotic protein Noxa controls selection of lymphocytes under competitive conditions
R.A.W. van Lier
- Award date
- 5 November 2010
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Darwinistic selection, or ‘survival of the fittest’, is based on intrinsic capacity, relative to that of its competitors in a given niche. This process drives the generation of species by allowing survival of organisms in with favorable, specialized characteristics for a certain niche. However, mere survival is not enough to obtain dominance. Selection only gets meaning when the ‘unfit’ organisms are actively eliminated from the population, thus generating space within the limited niche for the ‘fit’ organisms to thrive and expand. This thesis does not focus on Darwinistic selection for the generation of species, but for the formation of specialized cell subsets of the hematopoietic lineage within the same organism. Favorable features in this case are not bigger teeth or stronger legs, but enhanced receptors for survival factors and better control of suicide mechanisms. The process of elimination is not death of the organism, but cell death mediated by apoptosis. In our research we set out to investigate in vivo how members of the Bcl-2 family of pro- and anti-apoptotic proteins contribute to the selection of lymphocytes when they have to compete with each other for growth factors and nutrients based on their primary intrinsic feature: antigen affinity. We identify a prominent role for the pro-apoptotic protein Noxa, in interaction with its antagonist Mcl-1 and its ‘next of kin’ Bim. Cells of poor capacity are unable to prevent induction of apoptotic cell death via these proteins under competitive conditions and only the most specific cells can prevent their demise. Thus, in immune responses, proper control of apoptosis results in survival of only the fittest clone.
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