AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional activation in ovarian cancer cells.
The human homolog of the yeast cse1 gene (CSE1L) is over-expressed in ovarian cancer. CSE1L forms complex with Ran and importin-α and has roles in nucleocytoplasmic traffic and gene expression. CSE1L accumulated in the nucleus of ovarian cancer cell lines, while it was localized also in the cytoplasm of other cancer cell lines. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells, as the CSE1L protein translocated to the cytoplasm when AKT was inactivated. Moreover, the expression of a constitutively active AKT forced the translocation of CSE1L from the cytoplasm to the nucleus in other cancer cells. Nuclear accrual of CSE1L was associated to the nuclear accumulation of the phosphorylated Ran Binding protein 3 (RanBP3), which depended on AKT as well. Also in samples of human ovarian cancer, AKT activation was associated to nuclear accumulation of CSE1L and phosphorylation of RanBP3. Expression profiling of ovarian cancer cells after CSE1L silencing showed that CSE1L was required for the expression of genes promoting invasion and metastasis. In agreement, CSE1L silencing impaired motility and invasiveness of ovarian cancer cells. Altogether these data show that in ovarian cancer cells activated AKT by affecting RanBP3 phosphorylation determines the nuclear accumulation of CSE1L and likely the nuclear concentration of transcription factors conveying pro-oncogenic signals.
Department of Oncology, University of Torino School of Medicine, Torino, Italy; Institute for Cancer Research at Candiolo, Candiolo, Torino, Italy.
Annalisa
A
Lorenzato
Marta
M
Biolatti
Giuseppe
G
Delogu
Giampiero
G
Capobianco
Cristiano
C
Farace
Salvatore
S
Dessole
Antonio
A
Cossu
Francesco
F
Tanda
Roberto
R
Madeddu
Martina
M
Olivero
Maria Flavia
MF
Di Renzo
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism*; D029563:Cellular Apoptosis Susceptibility Protein / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D029563:Cellular Apoptosis Susceptibility Protein; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; C112820:RANBP3 protein, human; D051057:Proto-Oncogene Proteins c-akt
AKT1/AKT2; CSE1L; Chromosome segregation 1-like protein CSE1L; Expression profiling; Nuclear transport; Ovarian cancer; RSK; Ran; Ran-binding protein-3; RanBP3; Ras-related nuclear protein; chromosome segregation 1-like; ribosomal S6 kinase; v-akt murine thymoma viral oncogene homolog 1 and 2