Galectin-3 Translocates to the Perinuclear Membranes and Inhibits Cytochrome c Release from the Mitochondria

Abstract

Galectin-3 is a multifunctional oncogenic protein found in the nucleus and cytoplasm and also the extracellular milieu. Although recent studies demonstrated an anti-apoptotic activity of galectin-3, neither the functional site nor the mechanism of how galectin-3 regulates apoptosis is known. In this study, we examined the subcellular localization of galectin-3 during apoptosis and investigated its anti-apoptotic actions. We report that galectin-3 translocates to the perinuclear membrane following a variety of apoptotic stimuli. Confocal microscopy and biochemical analysis revealed that galectin-3 is enriched in the mitochondria and prevents mitochondrial damage and cytochrome c release. Using a yeast two-hybrid system, we screened for galectin-3-interacting proteins that regulate galectin-3 localization and anti-apoptotic activity. Synexin, a Ca2+- and phospholipid-binding protein, was one of the proteins identified. We confirmed direct interaction between galectin-3 and synexin by glutathioneS-transferase pull-down assay in vitro. We showed that galectin-3 failed to translocate to the perinuclear membranes when expression of synexin was down-regulated using an oligodeoxyribonucleotide complementary to the synexin mRNA, suggesting a role for synexin in galectin-3 trafficking. Furthermore, synexin down-regulation abolished anti-apoptotic activity of galectin-3. Taken together, these results suggest that synexin mediates galectin-3 translocation to the perinuclear mitochondrial membranes, where it regulates mitochondrial integrity critical for apoptosis regulation. Galectin-3 is a multifunctional oncogenic protein found in the nucleus and cytoplasm and also the extracellular milieu. Although recent studies demonstrated an anti-apoptotic activity of galectin-3, neither the functional site nor the mechanism of how galectin-3 regulates apoptosis is known. In this study, we examined the subcellular localization of galectin-3 during apoptosis and investigated its anti-apoptotic actions. We report that galectin-3 translocates to the perinuclear membrane following a variety of apoptotic stimuli. Confocal microscopy and biochemical analysis revealed that galectin-3 is enriched in the mitochondria and prevents mitochondrial damage and cytochrome c release. Using a yeast two-hybrid system, we screened for galectin-3-interacting proteins that regulate galectin-3 localization and anti-apoptotic activity. Synexin, a Ca2+- and phospholipid-binding protein, was one of the proteins identified. We confirmed direct interaction between galectin-3 and synexin by glutathioneS-transferase pull-down assay in vitro. We showed that galectin-3 failed to translocate to the perinuclear membranes when expression of synexin was down-regulated using an oligodeoxyribonucleotide complementary to the synexin mRNA, suggesting a role for synexin in galectin-3 trafficking. Furthermore, synexin down-regulation abolished anti-apoptotic activity of galectin-3. Taken together, these results suggest that synexin mediates galectin-3 translocation to the perinuclear mitochondrial membranes, where it regulates mitochondrial integrity critical for apoptosis regulation. (Asp-Glu-Val-Asp)ase phosphate-buffered saline fluorescein isothiocyanate raffinose 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside glutathione S-transferase Galectin-3 is a 31-kDa member of the β-galactoside-binding family of proteins found widely in epithelial and immune cells. Expression of galectin-3 is associated with neoplastic progression and metastatic potential (1Bresalier R.S. Yan P.S. Byrd J.C. Lotan R. Raz A. Cancer. 1997; 80: 776-787Crossref PubMed Scopus (163) Google Scholar, 2Konstantinov K.N. Robbins B.A. Liu F.T. Am. J. Pathol. 1996; 148: 25-30PubMed Google Scholar, 3Lotan R. Ito H. Yasui W. Yokozaki H. Lotan D. Tahara E. Int. J. Cancer. 1994; 56: 474-480Crossref PubMed Scopus (129) Google Scholar, 4Nangia-Makker P. Sarvis R. Visscher D.W. Bailey-Penrod J. Raz A. Sarkar F.H. Breast Cancer Res. Treat. 1998; 49: 171-183Crossref PubMed Scopus (39) Google Scholar, 5Raz A. Pazerini G. Carmi P. Cancer Res. 1989; 49: 3489-3493PubMed Google Scholar) in head and neck (6Xu A. Gillenwater X.C. el-Naggar A.K. Clayman G.L. Lotan R. Head Neck. 1996; 18: 422-432Crossref PubMed Google Scholar), thyroid (7Xu X.C. el-Naggar A.K. Lotan R. Am. J. Pathol. 1995; 147: 815-822PubMed Google Scholar), gastric (3Lotan R. Ito H. Yasui W. Yokozaki H. Lotan D. Tahara E. Int. J. Cancer. 1994; 56: 474-480Crossref PubMed Scopus (129) Google Scholar), and colon (8Schoeppner H.L. Ho A. Raz S.B. Bresalier R.S. Cancer. 1995; 75: 2818-2826Crossref PubMed Scopus (212) Google Scholar) cancers, suggesting a role in oncogenesis. Galectin-3 modulates a variety of cellular processes. Extracellular galectin-3 mediates cell migration, cell adhesion, and cell/cell interactions, whereas nuclear galectin-3 is involved in pre-mRNA splicing (9Le Marer N. Hughes R.C. J. Cell. Physiol. 1996; 168: 51-58Crossref PubMed Scopus (78) Google Scholar, 10Dagher S.F. Wang J.L. Patterson R.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1213-1217Crossref PubMed Scopus (354) Google Scholar, 11Wang L. Inohara H. Pienta K.J. Raz A. Biochem. Biophys. Res. Commun. 1995; 217: 292-303Crossref PubMed Scopus (84) Google Scholar). Interestingly, recent studies showed that cytoplasmic, but not nuclear, galectin-3 is associated with tumor progression (12van den Brule F.A. Waltregny D. Liu F.T. Castronovo V. Int. J. Cancer. 2000; 89: 361-367Crossref PubMed Google Scholar, 13Honjo Y. Inohara H. Akahani S. Yoshii T. Takenaka Y. Yoshida J. Hattori K. Tomiyama Y. Raz A. Kubo T. Clin. Cancer Res. 2000; 6: 4635-4640PubMed Google Scholar). Yet, the role of cytoplasmic galectin-3 is unknown. We (15Akahani S. Nangia-Makker P. Inohara H. Kim H.-R. Raz A. Cancer Res. 1997; 57: 5272-5276PubMed Google Scholar, 16Kim H.-R. Lin H.M. Biliran H. Raz A. Cancer Res. 1999; 59: 4148-4154PubMed Google Scholar, 17Lin H.M. Yu B.K. Moon F. Kim H.-R. Carcinogenesis. 2000; 21: 1941-1945Crossref PubMed Google Scholar) and others (14Yang R.Y. Hsu D.K. Liu F.T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6737-6742Crossref PubMed Scopus (660) Google Scholar, 18Matarrese P. Fusco O. Tinari N. Natoli C. Liu F.T. Semeraro M.L. Malorni W. Iacobelli S. Int. J. Cancer. 2000; 85: 545-554Crossref PubMed Scopus (208) Google Scholar, 19Matarresea P. Tinari N. Semeraroa M.L. Natolib C. Iacobelli S. Malorni W. FEBS Lett. 2000; 473: 311-315Crossref PubMed Scopus (130) Google Scholar) have previously shown that galectin-3 inhibits T-cell apoptosis induced by anti-Fas antibody and epithelial cell apoptosis induced by staurosporine, cisplatin, genistein, and anoikis. The anti-apoptotic activity of galectin-3 was also demonstrated in galectin-3-deficient mice. Peritoneal macrophages from galectin-3-deficient mice were more sensitive to apoptotic stimuli than those from control mice (20Hsu D.K. Yang R.Y. Yu Z. Pan L. Salomon D.R. Fung-Leung W.P. Liu F.T. Am. J. Pathol. 2000; 156: 1073-1083Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar). The ability of galectin-3 to protect cells against apoptosis induced by agents working through different mechanisms suggests that galectin-3 regulates the common apoptosis commitment step. During the past decade, explosive progress has been made toward understanding the molecular basis for the regulation of the apoptosis commitment step. Two major apoptotic pathways (intrinsic and extrinsic pathways) have been defined. Intrinsic apoptotic signaling induces cytochrome c release from the mitochondria. Cytosolic cytochrome c initiates the formation of an ∼700-kDa complex called the “apoptosome,” which consists of cytochromec, caspase adaptor proteins such as Apaf-1, and caspases (21Cain K. Brown D.G. Langlais C. Cohen G.M. J. Biol. Chem. 1999; 274: 22686-22692Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 22Zou H. Henzel W.J. Liu X. Lutschg A. Wang X. Cell. 1997; 90: 405-413Abstract Full Text Full Text PDF PubMed Scopus (2716) Google Scholar, 23Green D.R. Cell. 1998; 94: 695-698Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar). Apoptosome formation results in caspase activation, a commitment step for apoptosis induction. Extrinsic apoptotic signals are mediated by cell-surface death receptors, including Fas, tumor necrosis factor, and TRAIL receptor families. The death domain of the death receptor initiates the formation of the “death-inducing signaling complex,” where caspases are activated (reviewed in Ref.24Ashkenazi A. Dixit V.M. Science. 1998; 281: 1305-1308Crossref PubMed Scopus (5085) Google Scholar). Although a critical role for galectin-3 in apoptosis inhibition is now well documented, neither the functional site nor the molecular mechanism of how galectin-3 regulates apoptosis is understood. In this study, we investigate the subcellular localization of galectin-3 and its anti-apoptotic actions during intrinsic apoptosis in human breast epithelial cells (BT549). Here, we report that galectin-3 translocates to the perinuclear mitochondrial membranes and inhibits cytochrome c release following a variety of apoptotic stimuli. Whereas caspase activation is drastically down-regulated by galectin-3 overexpression in BT549 cells, exogenous cytochrome c effectively activates caspases in a cell-free system established from galectin-3-overexpressing cells. This suggests that galectin-3 protection of mitochondrial integrity is critical for its ability to down-regulate caspases. We identified synexin as a galectin-3-interacting protein using the yeast two-hybrid system and provide evidence that synexin is involved in galectin-3 translocation to the functional site for its anti-apoptotic actions. The human breast cancer cell line BT549 was obtained from Dr. E. W. Thompson (Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, D. C.). Galectin-3-transfected BT549 cells (BT549Gal-3) were previously established by introducing an expression vector containing human galectin-3 cDNA into parental BT549 cells (15Akahani S. Nangia-Makker P. Inohara H. Kim H.-R. Raz A. Cancer Res. 1997; 57: 5272-5276PubMed Google Scholar,16Kim H.-R. Lin H.M. Biliran H. Raz A. Cancer Res. 1999; 59: 4148-4154PubMed Google Scholar). The neomycin-resistant control vector-transfected BT549 cells are referred to as BT549neo. Cells were cultured using Dulbecco’s modified Eagle’s medium/nutrient mixture F-12 supplemented with 10% heat-inactivated fetal bovine serum, 100 units/ml penicillin, 100 μg/ml streptomycin, 2 mml-glutamine, and 0.5 μg/ml Fungizone in a 95% air and 5% CO2 incubator cell were from Cells were in cell and containing were for and of the was for in a of of caspase and containing of Using a by caspase was using activity was of protein by the protein assay Cells were in of apoptosis the cells were with containing for Cells were with and with in for The were with of the mitochondrial membrane was examined with a with a a in the Cells were and following with in containing and mixture and for The were through a and for The was by analysis using c antibody The of the was using the Cells were cultured to was induced by with for with 0.5 for by for Cells were with with in for with containing and with bovine in for with cells were with antibody c antibody for 2 with the were with for with the were with and examined a in the were using and The were for and by a was using the protein assay of protein in 10% 5% and were for and to the proteins were to a The was with 5% in and for The membranes were with the antibody in 5% in with the was with the The was using the system to the were as previously J. Liu X. K. Kim J. Wang X. Science. 1997; PubMed Scopus Google Scholar). and cells were in containing to protect mitochondria by using a were for to and The was for the which was in and of mitochondrial proteins was to Cells were in using a as previously Wang J.C. D.W. D.R. J. Biol. 1999; PubMed Scopus Google Scholar). The protein of the was using the protein assay and to from bovine was to cell-free to a of μg/ml and activity was as The yeast expression vector J. E. H. R. Cell. 75: Full Text PDF PubMed Scopus Google Scholar), which the for the domain and the yeast was to the The galectin-3 cDNA containing the was from the previously (15Akahani S. Nangia-Makker P. Inohara H. Kim H.-R. Raz A. Cancer Res. 1997; 57: 5272-5276PubMed Google Scholar) and with the The and were confirmed by Expression of the proteins was confirmed by The containing the protein was as yeast were as R. Expression University Scholar). raffinose The and are as containing was to yeast and The was yeast R. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar) containing R. Expression University Scholar) with the by R. Expression University Scholar). were by Expression of the protein was confirmed by analysis using and the the the was with Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar) containing vector J. E. H. R. Cell. 75: Full Text PDF PubMed Scopus Google Scholar), which was also to the cDNA The of and was The of was that the was and that the was for yeast two-hybrid The human tumor cDNA into the was obtained from and in yeast The was with the cDNA as previously Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, R. S. The University Scholar). of 2 were were and The that showed and were were from the by a yeast as previously R. Expression University Scholar). was using and to the The were with to The was into and The from the and were into yeast and were with containing the R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: PubMed Scopus Google Scholar), Z. T. R. D. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar), L. L. and R. L. and J. E. H. R. Cell. 75: Full Text PDF PubMed Scopus Google were as The that with but not with were The were using the containing and 100 μg/ml was with an of cells with the containing the human galectin-3 cDNA the cells were to an of was Cells were for an and by The was with and in 100 units/ml μg/ml μg/ml and The cells were by the was for and the were through an 100 The was made by the to to the and was well in and The was with of and the protein was with were using the protein assay and by and analysis using The expression for the protein was obtained from Dr. E. of The expression was obtained from Dr. The and proteins were as previously J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). expression of the and proteins was induced in E. cells by 100 for The cells were by in of with and by The was for The was with of the with the proteins were with of The proteins were against using In of galectin-3 to synexin was examined by pull-down assay as previously S. Wang J.L. Patterson R.J. Res. PubMed Scopus Google Scholar). were with of proteins in of was to of the for 2 and the were with of human galectin-3 proteins in of with was with the in the of of bovine for 2 In a control of galectin-3 protein in of was by for by the with the proteins were with of and to and The complementary to the human synexin the and the control containing were and by cells into which the were the were with the Cells were with using as by the 2 of was with of and of by for by for The was with of for by for The was with of and cells in to In control cells were with the mixture with the cells were and in for analysis in caspase for caspase activity with cells a in a were with the mixture of of of of and of of the was with and the cells were with and 0.5 for and with critical for apoptosis the of of mitochondrial and release of cytochrome c D.R. Cell. 1998; 94: 695-698Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar, Y. Science. 1998; 281: PubMed Scopus Google Scholar), in caspase galectin-3 mitochondrial we and cells with which mitochondria and as a for the mitochondrial membrane potential H.-R. Y. G. D. Cancer Res. 1999; 59: Google Scholar). of galectin-3 in cells was confirmed by analysis of with in the of mitochondrial in cells In the mitochondria in cells the as in the cells suggesting that galectin-3 overexpression cells against the of mitochondrial from the of mitochondrial the analysis of cytochrome c showed that the of from the mitochondria was in cells with cells following of a in cytochrome c was in cells, whereas an was in cells. the that cytochrome c was to the during the of cellular we of cytochrome c in control and apoptotic cells. The of cells cytochrome c following with In cytochrome c in cells following the Confocal analysis of cells with antibody and with confirmed that cytochrome c in the mitochondria in cells following apoptotic as shown results that galectin-3 overexpression cells from mitochondrial membrane potential and prevents cytochrome to the following a variety of apoptotic expression in human breast epithelial cells inhibits cytochrome c release from mitochondria in to apoptotic stimuli. and and cells were cultured with and with for and with for with 0.5 for and The mitochondria and cytochrome c were as and are of cytochrome c and mitochondria with the We previously showed that galectin-3 overexpression results in inhibition of following apoptotic stimuli (15Akahani S. Nangia-Makker P. Inohara H. Kim H.-R. Raz A. Cancer Res. 1997; 57: 5272-5276PubMed Google Scholar, 16Kim H.-R. Lin H.M. Biliran H. Raz A. Cancer Res. 1999; 59: 4148-4154PubMed Google Scholar), suggesting that galectin-3 caspase caspases as and the we and activity in and cells using the activity following in cells, whereas it following the in activity following 0.5 in cells, whereas was in cells results that the activity for apoptosis is by galectin-3 We galectin-3 inhibition of caspase activity results from in the apoptotic for caspase activation from inhibition of cytochrome c release. this we established a cell-free caspase activation system as previously Wang J.C. D.W. D.R. J. Biol. 1999; PubMed Scopus Google Scholar). in from human breast epithelial cells were effectively activated by cytochrome c and the activation were between and cell-free cell-free from cells caspases that activated in the of with the cell results that cells the to caspases and suggest that galectin-3 down-regulation of caspases results from its ability to release following apoptotic stimuli. the subcellular where galectin-3 its anti-apoptotic the galectin-3 protein in the control and apoptotic cells was with antibody and Galectin-3 was in the nucleus and cytoplasm in the control cells In galectin-3 a and membrane in cells with cultured in with This suggests that following apoptotic galectin-3 translocates to the to the where it prevents mitochondrial and inhibits caspase galectin-3 translocates to the cells were with antibody and The galectin-3 the mitochondrial following apoptotic but not those in the control cells and Confocal analysis from the of revealed that galectin-3 and mitochondria following apoptotic as shown by galectin-3 translocation to the mitochondria were in the of as previously J. Liu X. K. Kim J. Wang X. Science. 1997; PubMed Scopus Google Scholar). analysis confirmed a in the of galectin-3 protein in the mitochondrial following apoptotic stimuli The galectin-3 protein for its subcellular suggesting that galectin-3 translocation through its interaction with proteins that direct protein trafficking. for proteins that with galectin-3, we screened a human tumor cDNA using the yeast two-hybrid as J. E. H. R. Cell. 75: Full Text PDF PubMed Scopus Google Scholar, R. Expression University Scholar, Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). of 2 were cDNA were from the and in E. for The were into yeast cells and for by two-hybrid interaction with the with of the with galectin-3, but not with the analysis revealed that 2 of the for the synexin two-hybrid interaction showed between galectin-3 and synexin The proteins that the direct interaction between galectin-3 and we an in and proteins were from the expression system, and direct between synexin and galectin-3 proteins were by pull-down as and shown in galectin-3 to but not to effectively with galectin-3 in the of a of bovine whereas it failed to to galectin-3 that galectin-3 to synexin is is a member of the Ca2+- and phospholipid-binding family of proteins J. Biol. Chem. Full Text PDF PubMed Google Scholar). is to as a and as a X. G. H. G. J. H. D. E. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google C. N. S. F. P. J. K. K. R. R. Cell. Biol. 21: PubMed Scopus Google Scholar). the of synexin for galectin-3 and apoptosis we down-regulated synexin expression in cells using of the complementary to the synexin down-regulated synexin whereas control synexin expression was galectin-3 also whereas extracellular galectin-3 suggesting that synexin is involved in galectin-3 trafficking. We examined synexin expression is critical for subcellular of galectin-3 following apoptotic stimuli. cells into which were cells were with the with the with antibody showed that galectin-3 was in the nucleus and cytoplasm in cells and as in control cells Cells with of the of galectin-3 proteins whereas cells with of the of galectin-3 results are with those obtained by analysis that synexin down-regulation in down-regulation of galectin-3 apoptotic galectin-3 was to the perinuclear membranes in cells whereas it in cells with of galectin-3 proteins was shown in BT549 cells into which were and results that synexin expression is critical for galectin-3 expression and during We of galectin-3 translocation by down-regulation of synexin has the anti-apoptotic activity of galectin-3. We activity in cells with synexin down-regulation The of activity in cells were not by synexin down-regulation using activity following when synexin expression was This was to the of activation in cells following the that synexin down-regulation the ability of galectin-3 to down-regulate caspase activity. are a family of During the past decade, have been made to the of studies including revealed that of the family of proteins are of apoptosis (14Yang R.Y. Hsu D.K. Liu F.T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6737-6742Crossref PubMed Scopus (660) Google Scholar, S. Nangia-Makker P. Inohara H. Kim H.-R. Raz A. Cancer Res. 1997; 57: 5272-5276PubMed Google Scholar, 16Kim H.-R. Lin H.M. Biliran H. Raz A. Cancer Res. 1999; 59: 4148-4154PubMed Google Scholar, C. J. 1999; Google Scholar, J. K. A. J. Clin. 1997; PubMed Scopus Google Scholar, 1999; 6: PubMed Scopus Google Scholar). The is an of the tumor following such as and overexpression apoptosis K. Y. J.L. 1997; PubMed Scopus Google Scholar, F. A. T. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). The extracellular and proteins apoptosis in activated C. J. 1999; Google Scholar, J. K. A. J. Clin. 1997; PubMed Scopus Google Scholar). In studies (15Akahani S. Nangia-Makker P. Inohara H. Kim H.-R. Raz A. Cancer Res. 1997; 57: 5272-5276PubMed Google Scholar, 16Kim H.-R. Lin H.M. Biliran H. Raz A. Cancer Res. 1999; 59: 4148-4154PubMed Google Scholar) and others (14Yang R.Y. Hsu D.K. Liu F.T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6737-6742Crossref PubMed Scopus (660) Google Scholar) that but not galectin-3 inhibits the galectin-3 proteins were supplemented in the a of to 2 failed to protect BT549 cells against the containing galectin-3 by galectin-3-overexpressing cells (BT549Gal-3) failed to down-regulate apoptotic in BT549 cells, suggesting that extracellular galectin-3 anti-apoptotic activity not This that cytoplasmic galectin-3 regulates epithelial cell In with recent studies that cytoplasmic galectin-3 with tumor progression (12van den Brule F.A. Waltregny D. Liu F.T. Castronovo V. Int. J. Cancer. 2000; 89: 361-367Crossref PubMed Google Scholar, 13Honjo Y. Inohara H. Akahani S. Yoshii T. Takenaka Y. Yoshida J. Hattori K. Tomiyama Y. Raz A. Kubo T. Clin. Cancer Res. 2000; 6: 4635-4640PubMed Google Scholar), this provide an for the oncogenic activity of cytoplasmic galectin-3 in human cells. apoptotic galectin-3 is enriched in the membrane including the a regulation site for apoptosis induced by a variety of stimuli. a family effectively mitochondrial integrity and the caspase following intrinsic apoptotic family proteins in the mitochondrial and nuclear through membrane (reviewed in S. Science. 1998; 281: PubMed Scopus Google Scholar). The family proteins in the mitochondrial membrane are to with the complex and to regulate the of the family galectin-3 not have a membrane galectin-3 is of an domain containing and and a domain containing the site A. Pazerini G. Carmi P. Cancer Res. 1989; 49: 3489-3493PubMed Google Scholar). Galectin-3 that are in the domain of the This is critical for anti-apoptotic activity and its interaction with family 1994; PubMed Scopus Google Scholar). to the protein, of with in the of galectin-3 its anti-apoptotic (15Akahani S. Nangia-Makker P. Inohara H. Kim H.-R. Raz A. Cancer Res. 1997; 57: 5272-5276PubMed Google Scholar, 16Kim H.-R. Lin H.M. Biliran H. Raz A. Cancer Res. 1999; 59: 4148-4154PubMed Google Scholar). The galectin-3 protection of mitochondrial integrity from its ability to with family as previously (14Yang R.Y. Hsu D.K. Liu F.T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6737-6742Crossref PubMed Scopus (660) Google Scholar), galectin-3 with the mitochondrial complex and regulate its This its molecular is galectin-3 its anti-apoptotic activity the perinuclear mitochondrial in cell-free from cells effectively activated by of cytochrome This suggests that of cytochrome c are from the galectin-3 to inhibits apoptotic galectin-3 inhibition of cytochrome c release from the mitochondria is critical for apoptosis a member of the family of to membranes J. Biol. Chem. Full Text PDF PubMed Google Scholar, 1996; PubMed Scopus Google Scholar). Although the of synexin it has been to as a and as a and membrane J. Biol. Chem. Full Text PDF PubMed Google Scholar, 1996; PubMed Scopus Google Scholar, D. C. E. FEBS Lett. 2000; PubMed Scopus Google Scholar, Liu W. P. J. Sci. Google Scholar). Galectin-3 for its subcellular localization and is in the nucleus and is also by a mechanism of the has been that galectin-3 is to the membrane through an mechanism and through by release from the of synexin prevents galectin-3 translocation to the perinuclear membranes and galectin-3 This that synexin not direct galectin-3 but is for translocation of galectin-3. it that galectin-3 and translocation different pathways and that of galectin-3 localization the galectin-3 suggesting a between these regulates in a J. Biol. Chem. Full Text PDF PubMed Google 1996; PubMed Scopus Google Scholar, D. C. E. FEBS Lett. 2000; PubMed Scopus Google Scholar). Interestingly, galectin-3 was shown to by the which S. Hughes R.C. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar), suggesting that a for the between the galectin-3 We Dr. E. for the expression Dr. and for with and for with of the