Nuclear export of phosphorylated galectin-3 regulates its antiapoptotic activity in response to chemotherapeutic drugs.
Galectin-3 (Gal-3), a member of the beta-galactoside binding protein family containing the NWGR antideath motif of the Bcl-2 protein family, is involved in various aspects of cancer progression. Previously, it has been shown that the antiapoptotic activity of Gal-3 is regulated by the phosphorylation at Ser(6) by casein kinase 1 (CK1). Here we questioned how phosphorylation at Ser(6) regulates Gal-3 function. We have generated serine-to-alanine (S6A) and serine-to-glutamic acid (S6E) Gal-3 mutants and transfected them into the BT-549 human breast carcinoma cell line, which does not express Gal-3. BT-549 cell clones expressing wild-type (wt) and mutant Gal-3 were exposed to chemotherapeutic anticancer drugs. In response to the apoptotic insults, phosphorylated wt Gal-3 was exported from the nucleus to the cytoplasm and protected the BT-549 cells from drug-induced apoptosis while nonphosphorylated mutant Gal-3 neither was exported from the nucleus nor protected BT-549 cells from drug-induced apoptosis. Furthermore, leptomycin B, a nuclear export inhibitor, increased the cisplatin-induced apoptosis of Gal-3 expressing BT-549 cells. These results suggest that Ser(6) phosphoryaltion acts as a molecular switch for its cellular translocation from the nucleus to the cytoplasm and, as a result, regulates the antiapoptotic activity of Gal-3.
Takenaka
Yukinori
Y
Tumor Progression and Metastasis Program, Karmanos Cancer Institute, Detroit, Michigan 48201, USA.
Fukumori
Tomoharu
T
Yoshii
Tadashi
T
Oka
Natsuo
N
Inohara
Hidenori
H
Kim
Hyeong-Reh Choi
HR
Bresalier
Robert S
RS
Raz
Avraham
A
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D037502:Galectin 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D014162:Transfection
D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; D037502:Galectin 3; D011994:Recombinant Proteins; D012694:Serine; D002945:Cisplatin; C038753:leptomycin B