期刊
NATURE
卷 480, 期 7377, 页码 383-U139出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10595
关键词
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资金
- John Templeton Foundation [12793]
- Origin of Organismal Complexity
There is an emerging consensus that gene regulation evolves through changes in cis-regulatory elements(1,2) and transcription factors(3-6). Although it is clear how nucleotide substitutions in cis-regulatory elements affect gene expression, it is not clear how amino-acid substitutions in transcription factors influence gene regulation(4-10). Here we show that amino-acid changes in the transcription factor CCAAT/enhancer binding protein-beta (CEBPB, also known as C/EBP-beta) in the stem-lineage of placental mammals changed the way it responds to cyclic AMP/protein kinase A (cAMP/PKA) signalling. By functionally analysing resurrected ancestral proteins, we identify three amino-acid substitutions in an internal regulatory domain of CEBPB that are responsible for the novel function. These amino-acid substitutions reorganize the location of key phosphorylation sites, introducing a new site and removing two ancestral sites, reversing the response of CEBPB to GSK-3 beta-mediated phosphorylation from repression to activation. We conclude that changing the response of transcription factors to signalling pathways can be an important mechanism of gene regulatory evolution.
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