An active nuclear retention signal in the glucocorticoid receptor functions as a strong inducer of transcriptional activation.
The glucocorticoid receptor (GR) cycles between a naive chaperone-complexed form in the cytoplasm and a transcriptionally active steroid-bound nuclear form. Nuclear import of GR occurs rapidly and is mediated through the importin alpha/beta karyopherin import pathway. By contrast, nuclear export of GR occurs only slowly under most conditions, despite a dependence on active signaling. In this study we have defined a nuclear retention signal (NRS) in the hinge region of GR that actively opposes the nuclear export of GR as well as the nuclear export mediated through an ectopic CRM1-dependent nuclear export signal (NES). The GR NRS overlaps closely with the basic NL1 nuclear localization signal (NLS) but can be distinguished from NL1 by targeted mutagenesis. Substitution of the classical NLS from SV40 T antigen for the GR NL1 results in a receptor in which nuclear export is accelerated. Remarkably, although the SV40-modified GR remains predominantly nuclear in the presence of steroid and is recruited to transcriptional regulatory regions indistinguishably from wild-type GR, the substitution dramatically weakens the ability of GR to activate transcription of a mouse mammary tumor virus reporter gene. These results suggest that active nuclear retention of GR plays an integral role in glucocorticoid signaling.
Carrigan
Amanda
A
Department of Medicine, University of Ottawa, Ottawa Health Research Institute, Ottawa, Ontario K1Y 4K9, Canada.
Walther
Rhian F
RF
Salem
Houssein Abdou
HA
Wu
Dongmei
D
Atlas
Ella
E
Lefebvre
Yvonne A
YA
Haché
Robert J G
RJ
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics*
D000596:Amino Acids; D011965:Receptors, Glucocorticoid