Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells.
We previously showed that the Drosophila DNA binding homeodomain of Prospero included a 28 amino-acid sequence (HDA) that functions as a nuclear export signal. We describe here the identification of a protein we named Caliban, which can directly interact with the HDA. Caliban is homologous to human Sdccag1, which has been implicated in colon and lung cancer. Here we show that Caliban and Sdccag1 are mediators of nuclear export in fly and human cells, as interference RNA abrogates export of EYFP-HDA in normal fly and human lung cells. Caliban functions as a bipartite mediator nuclear export as the carboxy terminus binds HDA and the amino terminus itself functions as an NES, which directly binds the NES receptor Exportin. Finally, while non-cancerous lung cells have functional Sdccag1, five human lung carcinoma cell lines do not, even though Exportin still functions in these cells. Expression of fly Caliban in these human lung cancer cells restores EYFP-HDA nuclear export, reduces a cell's ability to form colonies on soft agar and reduces cell invasiveness. We suggest that Sdccag1 inactivation contributes to the transformed state of human lung cancer cells and that Caliban should be considered a candidate for use in lung cancer gene therapy.
Bi
Xiaolin
X
Laboratory of Biochemistry, NCI, NIH, Bethesda, MD 20892, USA.
Jones
Tamara
T
Abbasi
Fatima
F
Lee
Heuijung
H
Stultz
Brian
B
Hursh
Deborah A
DA
Mortin
Mark A
MA
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition; D002467:Cell Nucleus / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009687:Nuclear Proteins / Q000502:physiology*; D029543:Nucleocytoplasmic Transport Proteins; D021382:Protein Sorting Signals / Q000502:physiology; D016415:Sequence Alignment; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C506864:Clbn protein, Drosophila; D029721:Drosophila Proteins; D006131:Growth Inhibitors; C402404:NEMF protein, human; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D021382:Protein Sorting Signals; D025521:Tumor Suppressor Proteins