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W2077696520 abstract "Bax, a member of the Bcl-2 family of proteins, has been shown to promote apoptosis while other members of the family, including Bcl-XL and Bcl-2, inhibit cell death induced by a variety of stimuli. The mechanism by which Bax promotes cell death is poorly understood. In the present report, we assessed the ability of Bax to antagonize the death repressor activity of Bcl-XL during chemotherapy-induced apoptosis in the lymphoid cell line, FL5.12. Expression of wild-type Bax countered the repressor activity of Bcl-XL against cell death mediated by VP-16 and cisplatin. We performed site-directed mutagenesis of the BH1, BH2, and BH3 homology regions in Bax to determine the ability of wild-type and mutant Bax to heterodimerize with Bcl-XL and to antagonize the protective effect of Bcl-XL against chemotherapy-induced apoptosis. Bax proteins expressing alanine substitutions of the highly conserved amino acids glycine 108 in BH1, tryptophan 151 and 158 in BH2, and glycine 67 and aspartic acid 68 in BH3 retained their ability to promote chemotherapy-induced cell death that was inhibited by Bcl-XL and to form heterodimers with Bcl-XL. Bax proteins containing deletions of the most highly conserved amino acids in BH1 (Δ102-112) and BH2 (Δ151-159) maintained the ability of Bax to antagonize the death repressor activity of Bcl-XL and to associate with Bcl-XL. However, Bax with BH3 deleted did not form heterodimers with Bcl-XL, but retained its ability to counter the death repressor activity of Bcl-XL. These results demonstrate that the conserved BH3, but not BH1 or BH2, homology region of Bax is necessary for its interaction with Bcl-XL in mammalian cells. Furthermore, our results indicate that Bax does not require BH1, BH2, BH3, or heterodimerization with Bcl-XL to counter the death repressor activity of Bcl-XL. Therefore, Bax can antagonize Bcl-XL during VP-16 and, in a lesser degree, during cisplatin-induced cell death independent of its heterodimerization with Bcl-XL. Bax, a member of the Bcl-2 family of proteins, has been shown to promote apoptosis while other members of the family, including Bcl-XL and Bcl-2, inhibit cell death induced by a variety of stimuli. The mechanism by which Bax promotes cell death is poorly understood. In the present report, we assessed the ability of Bax to antagonize the death repressor activity of Bcl-XL during chemotherapy-induced apoptosis in the lymphoid cell line, FL5.12. Expression of wild-type Bax countered the repressor activity of Bcl-XL against cell death mediated by VP-16 and cisplatin. We performed site-directed mutagenesis of the BH1, BH2, and BH3 homology regions in Bax to determine the ability of wild-type and mutant Bax to heterodimerize with Bcl-XL and to antagonize the protective effect of Bcl-XL against chemotherapy-induced apoptosis. Bax proteins expressing alanine substitutions of the highly conserved amino acids glycine 108 in BH1, tryptophan 151 and 158 in BH2, and glycine 67 and aspartic acid 68 in BH3 retained their ability to promote chemotherapy-induced cell death that was inhibited by Bcl-XL and to form heterodimers with Bcl-XL. Bax proteins containing deletions of the most highly conserved amino acids in BH1 (Δ102-112) and BH2 (Δ151-159) maintained the ability of Bax to antagonize the death repressor activity of Bcl-XL and to associate with Bcl-XL. However, Bax with BH3 deleted did not form heterodimers with Bcl-XL, but retained its ability to counter the death repressor activity of Bcl-XL. These results demonstrate that the conserved BH3, but not BH1 or BH2, homology region of Bax is necessary for its interaction with Bcl-XL in mammalian cells. Furthermore, our results indicate that Bax does not require BH1, BH2, BH3, or heterodimerization with Bcl-XL to counter the death repressor activity of Bcl-XL. Therefore, Bax can antagonize Bcl-XL during VP-16 and, in a lesser degree, during cisplatin-induced cell death independent of its heterodimerization with Bcl-XL. INTRODUCTIONApoptosis, a morphologically distinguished form of programmed cell death, is critical not only during development and tissue homeostasis but also in the pathogenesis of a variety of diseases including cancer, autoimmune disease, viral infection, and neurodegenerative disorders (1Raff M.C. Nature. 1992; 356: 397-400Google Scholar, 2Williams G.T. Smith C.A. Cell. 1993; 74: 777-779Google Scholar, 3Fisher D.E. Cell. 1994; 78: 539-542Google Scholar, 4Martin S.J. Green D.R. Crit. Rev. Oncol. Hematol. 1995; 18: 137-153Google Scholar, 5Thompson C.B. Science. 1995; 267: 1456-1462Google Scholar, 6White E. Genes Dev. 1996; 10: 1-15Google Scholar). Moreover, many chemotherapy drugs used to treat cancers are thought to destroy tumor cells through activation of apoptosis (7Eastman A. Cancer Cells. 1990; 2: 275-280Google Scholar, 8Miyashita T. Reed J.C. Blood. 1993; 81: 151-157Google Scholar). The precise mechanisms that control apoptosis have not been elucidated; however, it appears that this form of cell death is regulated by a genetic program involving both effectors and repressors (6White E. Genes Dev. 1996; 10: 1-15Google Scholar). The bcl-2 gene, the first member of a rapidly expanding family of genes that regulate apoptosis, was initially isolated from the t(14:18) chromosomal translocation found in human B-cell follicular lymphomas and was subsequently shown to repress cell death triggered by a diverse array of stimuli (9Tsujimoto Y. Gorham J. Cossman J. Jaffe E. Croce C.M. Science. 1985; 229: 1390-1393Google Scholar, 10Vaux D.L. Cory S. Adams J.M. Nature. 1988; 335: 440-442Google Scholar, 11Nunez G. Clarke M.F. Trends Cell Biol. 1994; 4: 399-403Google Scholar). The Bcl-2 family of proteins share conserved regions termed Bcl-2 homology domain 1, 2, and 3 (BH1, BH2, and BH3) (12Yin X.M. Oltvai Z.N. Korsmeyer S.J. Nature. 1994; 369: 321-323Google Scholar, 13Chittenden T. Flemington C. Houghton A.B. Ebb G.E. Gallo G.J. Elangovan B. Chinnadurai G. Lutz R.J. EMBO J. 1995; 14: 5589-5596Google Scholar). Two other family members, Bax and Bcl-XL, are also known to regulate apoptosis. Bcl-XL represses cell death (14Boise L.H. Gonzalez-Garcia M. Postema C.E. Ding L. Lindsten T. Turka L.A. Mao X. Nunez G. Thompson C.B. Cell. 1993; 74: 597-608Google Scholar), while Bax counters the death repressor activity of Bcl-2 and accelerates cell death induced by growth factor withdrawal (15Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Cell. 1993; 74: 609-619Google Scholar). The biochemical mechanism by which Bcl-2 and Bcl-XL repress cell death is unknown. However, certain highly conserved amino acids within BH1 and BH2 are required for Bcl-2 to repress cell death and associate with Bax as shown by mutation analysis (12Yin X.M. Oltvai Z.N. Korsmeyer S.J. Nature. 1994; 369: 321-323Google Scholar). Although Bcl-2 repression of cell death is postulated to occur through heterodimerization with Bax (12Yin X.M. Oltvai Z.N. Korsmeyer S.J. Nature. 1994; 369: 321-323Google Scholar), mutations in Bcl-XL of these conserved regions showed that Bcl-XL can protect against apoptosis independently of Bax (16Cheng E.H.Y. Levine B. Boise L.H. Thompson C.B. Hardwick J.M. Nature. 1996; 379: 554-556Google Scholar). Thus, mutations which disrupted the association between Bcl-XL and Bax, still preserved 70-80% of the wild-type antiapoptotic activity of Bcl-XL, suggesting that Bcl-XL can protect against apoptosis independent of Bax (16Cheng E.H.Y. Levine B. Boise L.H. Thompson C.B. Hardwick J.M. Nature. 1996; 379: 554-556Google Scholar).Bak, another member of the Bcl-2 family of proteins, has been shown to both accelerate and inhibit apoptosis (17Chittenden T. Harrington E.A. O'Connor R. Flemington C. Lutz R.J. Evan G.I. Guild B.C. Nature. 1995; 374: 733-736Google Scholar, 18Farrow S.N. White J.H.M. Martinou I. Raven T. Pun K.T. Grinham C.J. Martinou J.C. Brown R. Nature. 1995; 374: 731-733Google Scholar, 19Kiefer M.C. Brauer M.J. Powers V.C. Wu J.J. Umansky S.R. Tomei L.D. Barr P.J. Nature. 1995; 374: 736-739Google Scholar). In FL5.12 cells deprived of interleukin 3 (IL-3), 1The abbreviations used are: IL-3interleukin 3HAhemagglutininPAGEpolyacrylamide gel electrophoresisPCRpolymerase chain reactionwtwild typemAbmonoclonal antibody. exogenous Bak expression promoted cell death and countered the antiapoptotic action of Bcl-2 (17Chittenden T. Harrington E.A. O'Connor R. Flemington C. Lutz R.J. Evan G.I. Guild B.C. Nature. 1995; 374: 733-736Google Scholar). Conversely, Bak overexpression inhibited cell death in the lymphoblastoid cell line, WI-L2, upon serum withdrawal and treatment with the cytotoxic agent menadione, in contrast to Bax that had no effect in this cell line (19Kiefer M.C. Brauer M.J. Powers V.C. Wu J.J. Umansky S.R. Tomei L.D. Barr P.J. Nature. 1995; 374: 736-739Google Scholar). Thus, Bak and Bax are able to accelerate cell death, but Bak unlike Bax can also inhibit cell death (17Chittenden T. Harrington E.A. O'Connor R. Flemington C. Lutz R.J. Evan G.I. Guild B.C. Nature. 1995; 374: 733-736Google Scholar), which suggests that they can act through different mechanisms. Structure and function analysis of Bak revealed that to interact with Bcl-XL, Bak required a region termed BH3 that is also conserved in Bax, Bcl-XL, and Bcl-2 (13Chittenden T. Flemington C. Houghton A.B. Ebb G.E. Gallo G.J. Elangovan B. Chinnadurai G. Lutz R.J. EMBO J. 1995; 14: 5589-5596Google Scholar). Although Bax has been shown to counter Bcl-2 during apoptosis triggered by IL-3 withdrawal (15Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Cell. 1993; 74: 609-619Google Scholar), its role in modulating Bcl-XL function is unclear. Furthermore, the function of the conserved homology regions of Bax have not been defined. In this report, we assessed the ability of Bax to modify the death repressor activity of Bcl-XL during chemotherapy-induced apoptosis. In addition, we performed site-directed mutational analysis of the conserved BH1, BH2, and BH3 homology regions of Bax to determine their functional requirement for Bax regulation of Bcl-XL activity in mammalian cells.DISCUSSIONIn the present study, we demonstrate that Bax can antagonize the death-suppressing activity of Bcl-XL. More importantly, we provide evidence that the interaction between Bax and Bcl-XL is not required for Bax to exert its death-accelerating activity during apoptosis mediated by chemotherapeutic drugs. This indicates that Bax can antagonize Bcl-XL and promote cell death independently of its association with Bcl-XL. However, Bax was unable to completely abrogate the protection afforded by Bcl-XL upon induction of cell death as previously reported for Bcl-2 (15Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Cell. 1993; 74: 609-619Google Scholar). A possible explanation for these findings is that the levels of Bax expressed by the cells were not high enough to completely reverse the protection afforded by Bcl-XL or Bcl-2. We have found, in additional experiments involving chemotherapy drugs, that the ability of wt Bax to counter the death repressor activity of Bcl-XL is enhanced with increasing amounts of Bax relative to that of Bcl-XL.2 If Bax accelerated cell death by inhibiting the ability of Bcl-XL to repress cell death through direct protein interactions, we would expect that disruption of Bax/Bcl-XL heterodimerization would result in loss of acceleration by Bax. Conversely, if Bcl-XL blocked cell death by inhibiting a death-promoting activity of Bax, we would expect that disruption of the Bax/Bcl-XL heterodimer would result in complete abrogation of the ability of Bcl-XL to block cell death. The finding that Bax did not completely abrogate the death-repressor activity of Bcl-XL suggests a model whereby the death-promoting Bcl-2 homologue Bax can block the protective effects of Bcl-2 and Bcl-XL through sequestration or competition for downstream cellular factors. Bax and Bcl-XL could compete directly for a common downstream molecule or indirectly through intermediate factors. Analysis of mutations in the BH1 and BH2 conserved regions of Bcl-XL revealed that the interaction between Bcl-XL and Bax is not required for Bcl-XL to protect against apoptosis induced by IL-3 withdrawal (16Cheng E.H.Y. Levine B. Boise L.H. Thompson C.B. Hardwick J.M. Nature. 1996; 379: 554-556Google Scholar). Together with our studies, the available data suggest that cell death can be regulated by Bcl-2 homologues at two distinct levels. First, death-promoting members such as Bax and death-suppressing members such as Bcl-XL can effect cell death independently perhaps through competition for cellular factors. Second, apoptosis can be controlled through heterodimerization between death-accelerating and death-repressing proteins such as Bax and Bcl-XL. The Bax/Bcl-XL interaction would result in the sequestration of free Bax or free Bcl-XL and either acceleration or inhibition of apoptosis depending on level of expression of each protein. This second mechanism considers Bax/Bcl-XL heterodimers as non-functional molecules as previously proposed for Bax and Bcl-2 (15Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Cell. 1993; 74: 609-619Google Scholar, 26Oltvai Z.N. Korsmeyer S.J. Cell. 1994; 79: 189-192Google Scholar). Alternatively, Bax may act upstream of Bcl-XL and promote apoptosis by enhancing a cell death signal which is inhibited by Bcl-XL or potentially, exogenous expression of Bax or Bcl-XL may induce endogenous expression of other known or yet undiscovered Bcl-2 family members. However, exogenous expression of Bax and Bcl-XL did not alter the endogenous levels of Bcl-2, Bcl-XL, or Bax when compared to the Neo control (data not shown).The present studies indicate that Bax, like Bak requires BH3 but not BH1 or BH2 to heterodimerize with Bcl-XL. Similarly, a region of Bax encompassing 28 amino acids that contained BH3 was sufficient to interact with Bcl-2 in yeast (27Han Z. Sabbatini P. Perez D. Rao L. Modha D. White E. Genes Dev. 1996; 10: 461-477Google Scholar). Our analysis showed that the BH3 domain of Bax is not necessary for Bax to promote chemotherapy-induced apoptosis that is inhibited by Bcl-XL. Therefore, in our experimental system, Bax did not require BH3 or interaction with Bcl-XL to promote apoptosis. In another study, however, Bak and Bax required BH3 to interact with Bcl-XL and also to induce cell death by transient transfection assays using Rat-1 fibroblasts (13Chittenden T. Flemington C. Houghton A.B. Ebb G.E. Gallo G.J. Elangovan B. Chinnadurai G. Lutz R.J. EMBO J. 1995; 14: 5589-5596Google Scholar). Several possibilities may explain the apparent discrepancy between the present results and those obtained by other investigators. First, the BH3 deletion mutant of Bax or Bak may have a differential effect on cell death depending on the cell line used for study. For example, the observation that Bak can act as both facilitator and inhibitor of cell death suggests that the cellular context of expression plays a role in determining biological activity (19Kiefer M.C. Brauer M.J. Powers V.C. Wu J.J. Umansky S.R. Tomei L.D. Barr P.J. Nature. 1995; 374: 736-739Google Scholar). Second, our analysis was performed in stable cell lines where induction of cell death required a specific apoptotic stimulus whereas the function of Bak and Bax in previous studies was determined in transient assays where the amount of proteins expressed by the cells could not be determined. It is possible, therefore, that the type of apoptotic signal or the level of gene expression is critical for the biological function observed in various systems. In agreement with our studies, other investigators have been able to develop stable cell lines after transfection of bax constructs into mammalian cells indicating that in certain cell lines, Bax overexpression does not induce cell death in the absence of a cell death signal (15Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Cell. 1993; 74: 609-619Google Scholar).We show in this report that Bax does not require BH1, BH2, or BH3 to exert it death-promoting activity while Bcl-2 and Bcl-XL require BH1 and BH2 for function. Bax, Bak and Bik, another putative member of the Bcl-2 family that promotes cell death (28Boyd J.M. Gallo G.J. Elangovan B. Houghton A.B. Malstrom S. Avery B.J. Ebb R.G. Subramanian T. Chittenden T. Lutz R.J. Chinnadurai G. Oncogene. 1995; 11: 1921-1928Google Scholar), share the conserved BH3 region. Importantly, Bcl-2 family members such as Bcl-2 and Bcl-XL that exhibit death suppressor activity also contain conserved amino acids in BH3 indicating that the death-accelerating properties of Bax and Bak cannot be explained solely by the presence of BH3. Although Bax, Bak, Bcl-XL, and Bcl-2 all contain BH1-3 domains, they appear to require different regions and amino acids for function and heterodimerization. When the conserved glycine in BH1 of Bcl-2 (glycine 145) is changed to an alanine, the Bax/Bcl-2 association is disrupted and Bcl-2 no longer can protect from cell death (12Yin X.M. Oltvai Z.N. Korsmeyer S.J. Nature. 1994; 369: 321-323Google Scholar). Mutations of amino acids 138 to 140 in BH1 of Bcl-XL also disrupted the Bax/Bcl-XL association as well as the ability of Bcl XL to block apoptosis (16Cheng E.H.Y. Levine B. Boise L.H. Thompson C.B. Hardwick J.M. Nature. 1996; 379: 554-556Google Scholar). However, in our analysis, Bax neither requires glycine 108 nor the most conserved amino acids in BH1 to promote cell death inhibited by Bcl-XL and to heterodimerize with Bcl-XL. In BH2, deletion of tryptophan 185 along with the adjoining 3 amino acids in Bcl-2 not only abrogated the ability of Bcl-2 to repress cell death induced by growth factor withdrawal, gamma irradiation, and glucocorticoids, but also disrupted heterodimerization between Bax and Bcl-2 (12Yin X.M. Oltvai Z.N. Korsmeyer S.J. Nature. 1994; 369: 321-323Google Scholar). Tryptophan 188 and aspartic acid 189 when changed to glycine and alanine, reduced the ability of Bcl-XL to delay cell death, but did not completely disrupt the Bax/Bcl-XL heterodimerization (16Cheng E.H.Y. Levine B. Boise L.H. Thompson C.B. Hardwick J.M. Nature. 1996; 379: 554-556Google Scholar). In our studies Bax neither required the conserved tryptophans 151 and 158 nor the most conserved amino acids in BH2 to promote cell death inhibited by Bcl-XL and to heterodimerize with Bcl-XL. Although both BH1 and BH2 domains are required for Bcl-XL and Bcl-2 death-repressor function, Bax does not require BH1 or BH2 to antagonize the ability of Bcl-XL to repress cell death or to heterodimerize with Bcl-XL in mammalian cells. Thus, Bax, Bcl-XL, and Bcl-2 appear to have different functional requirements for each one of the conserved domains as well as conserved amino acids within each domain. These observations suggest a model whereby different conserved regions of Bcl-2 homologues interact in a nonsymetrical manner between certain members of the Bcl-2 family of proteins. The precise intramolecular and intermolecular structure of Bcl-2 family members are presently unresolved and need to be addressed in future studies. INTRODUCTIONApoptosis, a morphologically distinguished form of programmed cell death, is critical not only during development and tissue homeostasis but also in the pathogenesis of a variety of diseases including cancer, autoimmune disease, viral infection, and neurodegenerative disorders (1Raff M.C. Nature. 1992; 356: 397-400Google Scholar, 2Williams G.T. Smith C.A. Cell. 1993; 74: 777-779Google Scholar, 3Fisher D.E. Cell. 1994; 78: 539-542Google Scholar, 4Martin S.J. Green D.R. Crit. Rev. Oncol. Hematol. 1995; 18: 137-153Google Scholar, 5Thompson C.B. Science. 1995; 267: 1456-1462Google Scholar, 6White E. Genes Dev. 1996; 10: 1-15Google Scholar). Moreover, many chemotherapy drugs used to treat cancers are thought to destroy tumor cells through activation of apoptosis (7Eastman A. Cancer Cells. 1990; 2: 275-280Google Scholar, 8Miyashita T. Reed J.C. Blood. 1993; 81: 151-157Google Scholar). The precise mechanisms that control apoptosis have not been elucidated; however, it appears that this form of cell death is regulated by a genetic program involving both effectors and repressors (6White E. Genes Dev. 1996; 10: 1-15Google Scholar). The bcl-2 gene, the first member of a rapidly expanding family of genes that regulate apoptosis, was initially isolated from the t(14:18) chromosomal translocation found in human B-cell follicular lymphomas and was subsequently shown to repress cell death triggered by a diverse array of stimuli (9Tsujimoto Y. Gorham J. Cossman J. Jaffe E. Croce C.M. Science. 1985; 229: 1390-1393Google Scholar, 10Vaux D.L. Cory S. Adams J.M. Nature. 1988; 335: 440-442Google Scholar, 11Nunez G. Clarke M.F. Trends Cell Biol. 1994; 4: 399-403Google Scholar). The Bcl-2 family of proteins share conserved regions termed Bcl-2 homology domain 1, 2, and 3 (BH1, BH2, and BH3) (12Yin X.M. Oltvai Z.N. Korsmeyer S.J. Nature. 1994; 369: 321-323Google Scholar, 13Chittenden T. Flemington C. Houghton A.B. Ebb G.E. Gallo G.J. Elangovan B. Chinnadurai G. Lutz R.J. EMBO J. 1995; 14: 5589-5596Google Scholar). Two other family members, Bax and Bcl-XL, are also known to regulate apoptosis. Bcl-XL represses cell death (14Boise L.H. Gonzalez-Garcia M. Postema C.E. Ding L. Lindsten T. Turka L.A. Mao X. Nunez G. Thompson C.B. Cell. 1993; 74: 597-608Google Scholar), while Bax counters the death repressor activity of Bcl-2 and accelerates cell death induced by growth factor withdrawal (15Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Cell. 1993; 74: 609-619Google Scholar). The biochemical mechanism by which Bcl-2 and Bcl-XL repress cell death is unknown. However, certain highly conserved amino acids within BH1 and BH2 are required for Bcl-2 to repress cell death and associate with Bax as shown by mutation analysis (12Yin X.M. Oltvai Z.N. Korsmeyer S.J. Nature. 1994; 369: 321-323Google Scholar). Although Bcl-2 repression of cell death is postulated to occur through heterodimerization with Bax (12Yin X.M. Oltvai Z.N. Korsmeyer S.J. Nature. 1994; 369: 321-323Google Scholar), mutations in Bcl-XL of these conserved regions showed that Bcl-XL can protect against apoptosis independently of Bax (16Cheng E.H.Y. Levine B. Boise L.H. Thompson C.B. Hardwick J.M. Nature. 1996; 379: 554-556Google Scholar). Thus, mutations which disrupted the association between Bcl-XL and Bax, still preserved 70-80% of the wild-type antiapoptotic activity of Bcl-XL, suggesting that Bcl-XL can protect against apoptosis independent of Bax (16Cheng E.H.Y. Levine B. Boise L.H. Thompson C.B. Hardwick J.M. Nature. 1996; 379: 554-556Google Scholar).Bak, another member of the Bcl-2 family of proteins, has been shown to both accelerate and inhibit apoptosis (17Chittenden T. Harrington E.A. O'Connor R. Flemington C. Lutz R.J. Evan G.I. Guild B.C. Nature. 1995; 374: 733-736Google Scholar, 18Farrow S.N. White J.H.M. Martinou I. Raven T. Pun K.T. Grinham C.J. Martinou J.C. Brown R. Nature. 1995; 374: 731-733Google Scholar, 19Kiefer M.C. Brauer M.J. Powers V.C. Wu J.J. Umansky S.R. Tomei L.D. Barr P.J. Nature. 1995; 374: 736-739Google Scholar). In FL5.12 cells deprived of interleukin 3 (IL-3), 1The abbreviations used are: IL-3interleukin 3HAhemagglutininPAGEpolyacrylamide gel electrophoresisPCRpolymerase chain reactionwtwild typemAbmonoclonal antibody. exogenous Bak expression promoted cell death and countered the antiapoptotic action of Bcl-2 (17Chittenden T. Harrington E.A. O'Connor R. Flemington C. Lutz R.J. Evan G.I. Guild B.C. Nature. 1995; 374: 733-736Google Scholar). Conversely, Bak overexpression inhibited cell death in the lymphoblastoid cell line, WI-L2, upon serum withdrawal and treatment with the cytotoxic agent menadione, in contrast to Bax that had no effect in this cell line (19Kiefer M.C. Brauer M.J. Powers V.C. Wu J.J. Umansky S.R. Tomei L.D. Barr P.J. Nature. 1995; 374: 736-739Google Scholar). Thus, Bak and Bax are able to accelerate cell death, but Bak unlike Bax can also inhibit cell death (17Chittenden T. Harrington E.A. O'Connor R. Flemington C. Lutz R.J. Evan G.I. Guild B.C. Nature. 1995; 374: 733-736Google Scholar), which suggests that they can act through different mechanisms. Structure and function analysis of Bak revealed that to interact with Bcl-XL, Bak required a region termed BH3 that is also conserved in Bax, Bcl-XL, and Bcl-2 (13Chittenden T. Flemington C. Houghton A.B. Ebb G.E. Gallo G.J. Elangovan B. Chinnadurai G. Lutz R.J. EMBO J. 1995; 14: 5589-5596Google Scholar). Although Bax has been shown to counter Bcl-2 during apoptosis triggered by IL-3 withdrawal (15Oltvai Z.N. Milliman C.L. Korsmeyer S.J. Cell. 1993; 74: 609-619Google Scholar), its role in modulating Bcl-XL function is unclear. Furthermore, the function of the conserved homology regions of Bax have not been defined. In this report, we assessed the ability of Bax to modify the death repressor activity of Bcl-XL during chemotherapy-induced apoptosis. In addition, we performed site-directed mutational analysis of the conserved BH1, BH2, and BH3 homology regions of Bax to determine their functional requirement for Bax regulation of Bcl-XL activity in mammalian cells." @default.
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W2077696520 title "Bax Can Antagonize Bcl-XL during Etoposide and Cisplatin-induced Cell Death Independently of Its Heterodimerization with Bcl-XL" @default.
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