Glucocorticoid-induced leucine zipper (GILZ) promotes the nuclear exclusion of FOXO3 in a Crm1-dependent manner.
GILZ (glucocorticoid-induced leucine zipper) is an ubiquitous protein whose expression is induced by glucocorticoids in lymphoid cells. We previously showed that GILZ expression is rapidly induced upon interleukin 2 deprivation in T-cells, protecting cells from apoptosis induced by forkhead box subgroup O3 (FOXO3). The aim of this work is to elucidate the molecular mechanism of FOXO factor inhibition by GILZ. We show in the myeloid cell line HL-60 and the lymphoid CTLL-2 T-cell line that GILZ down-regulates the expression of p27(KIP1) and Bim, two FOXO targets involved in cell cycle regulation and apoptosis, respectively. GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. This inhibitory effect is independent of protein kinase B and IkappaB kinase phosphorylation sites. GILZ does not hinder FOXO3 DNA-binding activity and does not physically interact with FOXO3. However, using fluorescence microscopy, we observe that GILZ expression provokes a Crm-1-dependent nuclear exclusion of FOXO3 leading to its relocalization to the cytoplasm. Moreover, GILZ exclusive cytoplasmic localization is a prerequisite for FOXO3 inhibition and relocalization. We propose that GILZ is a general inhibitor of FOXO factors acting through an original mechanism by preventing them from reaching target genes within the nucleus.
Latré de Laté
Perle
P
INSERM UMR-S 749, Faculté de Pharmacie, and INSERM, Université Paris-Sud 11, 92296 Châtenay-Malabry, France.
Pépin
Aurélie
A
Assaf-Vandecasteele
Hind
H
Espinasse
Christophe
C
Nicolas
Valérie
V
Asselin-Labat
Marie-Liesse
ML
Bertoglio
Jacques
J
Pallardy
Marc
M
Biola-Vidamment
Armelle
A
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000097606:Exportin 1 Protein; C436291:CDKN1B protein, human; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C108803:FOXO4 protein, human; C508594:IL2 protein, human; C404226:TSC22D3 protein, human