Discovery of PQM-1 as a key regulator of aging and longevity.

diagram showing antagonism between DAF-16 and PQM-1

Aging is fundamental to the human life cycle and intimately connected with disease. Understanding the genetic and molecular determinants of animal longevity will provide new avenues for slowing the negative effects of aging. Using the nematode C. elegans as a model organism, and applying a combination of computational and experimental methodsin close collaboration with the lab of Dr. Coleen Murphy at Princeton University, Ronald Tepper in the Bussemaker lab has discovered (Tepper et al., Cell, 2013) that the little-studied transcription factor PQM-1 is a key regulator of development and longevity, and the long-sought factor that binds the so-called DAF-16 associated element (DAE). As it turns out, PQM-1 complements the well-known aging transcription factor DAF-16/FOXO in many respects. Both act as transcriptional activators, but they control distinct sets of target genes (stress response vs. growth). Whether DAF-16 or PQM-1 is nuclear or cytoplasmic depends on the status of the insulin/IGF-1 signaling pathway, but in opposite ways. This causes only one of the factors to be active as a regulator at any given time, depending on the conditions (e.g. low nutrients) and genetic background (e.g., loss of daf-2 or daf-18/PTEN). At the same time, as we have shown, the two factors interact with each other in an essential way: loss of pqm-1 affects DAF-16 subcellular localization, and vice versa. The molecular mechanisms underlying these important processes, however, remain obscure.

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