Bax

Bax Background

As a member of the Bax subfamily that belongs to the Bcl-2 family of proteins, Bcl-2-associated X protein (BAX) is a pro-apoptotic protein encoded by the BAX gene ^[1]. BAX contains conserved Bcl-2 homology domains (BH1, BH2, BH3, and BH4)and a hydrophobic region at the C-terminal ends that are believed to serve as a membrane-spanning domain ^[1][2]. BAX expression is regulated by the tumor suppressor P53, and it is involved in P53-mediated apoptosis. Although the subcellular localization of Bax has not been known, Bax has been suggested to colocalize within the same subcellular compartments as Bcl-2 due to the presence of its putative C-terminal transmembrane segment and its ability to dimerize with Bcl-2 ^[3]. A majority of BAX proteins are found in the cytosol before apoptosis induction ^[4][5]. Upon the induction of apoptotic signals, BAX undergoes a conformation alteration, making itself translocate from the cytosol to mitochondria ^[4][5] where it participates in mitochondrial disruption and the release of cytochrome c. The loss of cytochrome c from mitochondria disables energy production, and cytosolic cytochrome c triggers a proteolytic cascade that dismantles the cell, namely apoptosis. Regulating the insertion of BAX into the mitochondrial outer membrane can regulate apoptosis ^[6][7]. Extensive mutagenesis studies have shown that the docking of BAX to mitochondria is dependent on its C-terminal sequence. The conformational change of the BAX C-terminus exposes the hydrophobic BH3 binding pocket that is involved in dimer formation, thus modulating the subcellular location of BAX and apoptosis ^[8]. Studies have proved that drugs such as ABT737 and a BH3 mimetic, that activate BAX, are the potential to be anticancer therapies by inducing apoptosis in cancer cells ^[9].

[1] Adams J.M., Cory S. The Bcl-2 protein family [J]. Science. 1998; 281: 1322-1326.
[2] Gross A., McDonnell J.M., et al. BCL-2 family members and the mitochondria in apoptosis [J]. Genes Dev. 1999; 13: 1899-1911.
[3] Oltvai Z N, Milliman C L, et al. Bcl-2 Heterodimerizes in Vivo With a Conserved Homolog, Bax, That Accelerates Programmed Cell Death [J]. Cell. 1993;74:609-619.
[4] Hsu Y.T., Wolter K.G., et al. Cytosol-to-membrane redistribution of Bax and Bcl-XL during apoptosis [J]. Proc. Natl. Acad. Sci. USA. 1997; 94: 3668-3672.
[5] Wolter K.G., Hsu Y.T., et al. Movement of Bax from the cytosol to mitochondria during apoptosis [J].J. Cell Biol. 1997; 139: 1281-1292.
[6] Goping I.S., Gross A., et al. Regulated targeting of BAX to mitochondria [J]. J. Cell Biol. 1998; 143: 207-215.
[7] Gross A., Jockel J., et al. Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis [J]. EMBO J. 1998; 17: 3878-3885.
[8] Nechushtan A., Smith C.L., et al. Conformation of the Bax C-terminus regulates subcellular location and cell death [J]. EMBO J. 1999; 18: 2330-2341.
[9] Westphal, D, Kluck, RM, et al. Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis [J]. Cell Death ＆ Differentiation. February 2014, 21 (2): 196-205.