Disease relevance of Bak1

• Caspase-2 triggers Bax-Bak-dependent and -independent cell death in colon cancer cells treated with resveratrol [1].
• Bak and Bax function to limit adenovirus replication through apoptosis induction [2].
• Furthermore, inducible deletion of Bax and Bak in adult mice results in the development of severe autoimmune disease [3].
• Benzyl isothiocyanate-induced apoptosis in human breast cancer cells is initiated by reactive oxygen species and regulated by Bax and Bak [4].
• Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria [5].

High impact information on Bak1

• Pro-survival Bcl-x(L) constrains the pro-apoptotic activity of Bak to maintain platelet survival, but as Bcl-x(L) degrades, aged platelets are primed for cell death [6].
• The antagonistic balance between Bcl-x(L) and Bak constitutes a molecular clock that determines platelet life span: this represents an important paradigm for cellular homeostasis, and has profound implications for the diagnosis and treatment of disorders that affect platelet number and function [6].
• However, using growth factor-dependent cells from Bax/Bak-deficient mice, we demonstrate that apoptosis is not essential to limit cell autonomous survival [7].
• Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak [8].
• The widespread tissue distribution of Bak messenger RNA, including those containing long-lived, terminally differentiated cell types, suggests that cell-death-inducing activity is broadly distributed, and that tissue-specific modulation of apoptosis is controlled primarily by regulation of molecules that inhibit apoptosis [8].

Biological context of Bak1

• Thus, the function of either Bax or Bak appears required to initiate most forms of apoptosis and to suppress oncogenic transformation [9].
• Combined loss of proapoptotic genes Bak or Bax with Bim synergizes to cause defects in hematopoiesis and in thymocyte apoptosis [10].
• Bak and Bax are functionally redundant in non-neuronal cells and represent a mitochondrial convergence point for cell death signaling pathways [11].
• N-Bak message and protein levels are elevated in cortical neurons in response to DNA damage, and subsequent induction of neuronal death is significantly delayed by expressing a full-length Bak antisense plasmid [11].
• Furthermore, Bax and Bak deficiency dramatically increased E1A expression and virus replication [2].

Anatomical context of Bak1

• Furthermore, whereas mouse embryo fibroblasts (MEF) expressing only Bax or Bak displayed resistance to transformation, bax(-/-)bak(-/-) MEF were nearly as prone to oncogenic transformation as p53(-/-) MEF [9].
• Bak protein was present in early erythroblasts, but diminished progressively during differentiation [12].
• N-Bak interacts with Bcl-XL but not BAX, suggesting an indirect mechanism for promoting Bax translocation to the mitochondria [11].
• Overexpression of N-Bak promotes Bax translocation in HeLa cells and induces neuronal cell death in cortical, hippocampal, and cerebellar granule neurons in a Bax-dependent manner [11].
• In the present study, we demonstrate that postnatal cortical and cerebellar granule neurons exclusively express an alternatively spliced, BH3 domain-only form of Bak (N-Bak), whereas astrocytes express only the full-length, multidomain form [11].

Associations of Bak1 with chemical compounds

• These results suggest that neither activation of BH3-only proteins nor suppression of pro-survival Bcl-2 proteins is sufficient to kill cells in the absence of both Bax and Bak [9].
• tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak [13].
• N-Bak is generated by neuron-specific splicing of a novel 20-base pair exon, which changes the previously described Bak, containing Bcl-2 homology (BH) domains BH1, BH2, and BH3, into a shorter BH3-only protein [14].
• Activation of Bak, Bax, and BH3-only proteins in the apoptotic response to doxorubicin [15].
• In this study, we found that NPCs deficient in Apaf-1, or both the pro-apoptotic multidomain Bcl-2 family members Bax and Bak, were resistant to cytosine arabinoside and gamma-irradiation-induced apoptosis [16].

Physical interactions of Bak1

• We demonstrate that antimycin A and a Bak BH3 peptide bind competitively to recombinant Bcl-2 [17].
• Bak interacts with Mfn1 and Mfn2, two mitochondrial fusion proteins [18].

Regulatory relationships of Bak1

• These findings provide the first evidence that a proapoptotic Bcl-2 family protein induces apoptosis exclusively via Bak [19].
• However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage [20].
• Bax and Bak independently promote cytochrome C release from mitochondria [21].
• Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation [22].
• CONCLUSIONS: The enhanced expression of Bax, Bak proteins may play a role in hepatocyte apoptosis induced by TNF-alpha and D-galactosamine [23].

Other interactions of Bak1

• The expression of the pro-apoptotic members Bax, Bak, Bid, and Bcl-x(S) was significantly ( P < 0.05) decreased after TPN [24].
• These data suggest an essential overlapping role for Bak or Bax and Bim in the intrinsic apoptotic pathway [10].
• While mutation of Bak had no effect, ablation of Bax suppressed the loss of Sertoli cells in Bclw mutants [25].
• Bak was barely detectable and Bad protein level decreased in cells undergoing apoptosis [26].
• Soy decreased Bak and increased COX-2 and ER-alpha expression site-specifically in female mice [27].

Analytical, diagnostic and therapeutic context of Bak1

• Animal models suggest that Bax and Bak play an essential role in the implementation of apoptosis and as a result can hinder tumorigenesis [28].
• However, whereas combination treatment applied to in vitro cell culture was characterized by a significant up-regulation and activation of Bax and down-regulation of Bcl-xL, the treatment applied to tumors induced Bak and Bcl-xS, whereas Bcl-omega and Bcl-xL were down-regulated [29].
• Furthermore, using immunocytochemistry as well as chemical blocking of putative apical pathways we could demonstrate that Bak is activated prior to Bax [15].
• Immunoblotting revealed that the protein profiles of Bax, Bak and Bad were different during the progression of neuronal apoptosis in the LGN [30].
• HN peptide inhibits tBid-induced oligomerization of Bax and Bak in mitochondrial membranes, as shown by experiments with chemical cross-linkers or gel filtration [31].

References