Prolyl Isomerases and Nuclear Function

(calcium-signal modulating cyclophilin ligand), and Cyp40 is part of the Hsp90/Hsc70 complex that binds steroid receptors. Likewise, FKBP12 is a subunit of two calcium Tony Hunter Molecular Biology and Virology Laboratory The Salk Institute channels (the ryanodine receptor and the IP 3 receptor), 10010 North Torrey Pines Road is needed for the function of the MDR drug efflux pump La Jolla, California 92037-1099 in yeast, and interacts with type 1 TGF␤ receptors. This diverse collection of targets suggests that PPIases play a role in a wide variety of cellular processes. Despite their lack of structural similarity, the cyclophilins and The activity of transcription factors in eukaryotic cells FKBPs do have a common property, namely that they can be controlled by posttranslational modification, in-interact stably with the calcium-regulated protein phos-teraction with inhibitory proteins, and cytoplasmic se-phatase, known as calcineurin or PP2B, when bound to questration. In this regard a number of different types CsA and FK506 respectively. Indeed, it is the sequestra-of enzyme are known to regulate transcription factor tion and inhibition of calcineurin in lymphocytes that function. For instance, phosphorylation and dephos-prevents these cells from responding to antigen-induced phorylation by protein kinases and phosphatases are mitogenic signals, thus resulting in immunosuppression. well-established mechanisms for modulating transcrip-Despite the evidence that cyclophilins and FKBPs tion factor activity. Protein-lysine acetylases are the lat-have specific physiological targets, genetic analysis of est newcomers to the catalog of enzymes that can PPIase function in budding yeast has yielded a surpris-regulate transcription factors through posttranslational ing result. All the known members of the cyclophilin and modification. A recent paper in the January issue of FKBP families can be disrupted, and the cells survive Molecular Cell (Leverson and Ness, 1998) now adds although they grow slowly (Dolinski et al., 1997a). The another possible mechanism of enzymatic regulation to only essential PPIase in yeast is Ess1p, which is the the list. Leverson and Ness report that the DNA-binding homolog of the mammalian parvulin family PPIase Pin1. activity of the c-Myb transcription factor is negatively Cells depleted of Ess1p arrest in mitosis, whereas over-regulated by a stable interaction with Cyp40, a member expression of Pin1 delays HeLa cells in G2, consistent of the cyclophilin family of peptidyl-prolyl isomerases. with a role for Ess1p/Pin1 in progression into and Peptidyl-Prolyl Isomerases through M phase (Lu et al., 1996). Interestingly, the There are three families of peptidyl-prolyl isomerases Drosophila homolog of Ess1p, Dodo, …