Characterizing Inhibitor of Growth (ING) family evolution and ING1 structure and function

Abstract

The INhibitior of Growth (ING) family of tumor suppressors have emerged as a versatile family of phospholipid effectors, histone mark sensors, and growth regulators. An updated phylogenetic analysis of this protein family using sequences from 42 eukaryotic species reveals that ING4 is likely most similar to the ancestral ING protein, not ING3 as previously reported. Previous studies have shown that the major ING1 isoforms, ING1a and ING1b serve distinct cellular functions by differentially regulating apoptosis and senescence in primary cells. The ING1a isoform encodes a sequence unique in the human proteome. To identify ING1a homologs in other species we searched all available databases and found that sequences corresponding to ING1a were only found in great apes and Old-World monkeys. However, only select primates had start codons capable of encoding full-length ING1a. Moreover, when we expressed ING1a with and without it’s unique N-terminal sequence, the unique sequence promoted localization to the mitochondria. Given the natural induction of this isoform as cells age in culture, expression of ING1a may serve to help limit the replicative lifespan of cells from long-lived primates, in part through its activity in the mitochondria.