Disease relevance of BAK1

• These same v-BCL-2 proteins cooperate with loss of retinoblastoma protein and p53 tumor suppressor function, by inactivating the BAX and BAK apoptotic pathway to promote epithelial solid tumor growth and resistance to chemotherapy [1].
• In this study, we explored the therapeutic effects of gene transfer mediated elevations in BAK expression on human gastric cancer cells in vitro [2].
• Moreover, mutations of the BAK gene have been identified in human gastrointestinal cancers, suggesting that a perturbation of BAK-mediated apoptosis may contribute to the pathogenesis of gastric cancer [2].
• Expression of adenovirus E1A deregulates cell proliferation to facilitate viral DNA replication, prompting the initiation of apoptosis signaled primarily through proapoptotic BAK in productively infected cells [3].
• The close linkage of the BAK and CSBP genes to the MHC is of interest because of their possible involvement in autoimmune disease [4].

High impact information on BAK1

• Furthermore, we modeled a complex of BCL-XL and BID by aligning the BID and BAK BH3 motifs in the known BCL-XL-BAK BH3 complex [5].
• Thus, activation of a "multidomain" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli [6].
• BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis [7].
• Thus, MCL-1 may function by maintaining BAK in an inactive state, and the loss of MCL-1 upon activation of the DNA damage response, perhaps through replication stress induced in virus infected cells, may be required to initiate the apoptotic response [3].
• BAK/BAX-mediated mitochondrial outer-membrane permeabilization (MOMP) drives cell death during development and tissue homeostasis from zebrafish to humans [8].

Chemical compound and disease context of BAK1

• Overexpression of Etk in prostate cancer cells results in inhibition of p53 transcriptional activity and its interaction with the mitochondrial protein BAK and confers the resistance to doxorubicin [9].
• OBJECTIVES: Using a human in vitro model we have previously identified so-called bacillus Calmette-Guérin (BCG)-activated killer (BAK) cells as potential effector cells in BCG immunotherapy [10].

Biological context of BAK1

• In PgR+ cell lines and in concordance with the protective effect, the pro-apoptotic HRK and BAK1 mRNAs were up-regulated after apoptosis induction, while they were no more induced in condition of protection against apoptosis after MPA treatment [11].
• Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-X(L)-MCL-1 [12].
• RT-PCR and Western Blotting detected cellular BAK gene expression [2].
• RESULTS: BAK gene transfer could result in significant BAK overexpression, decreased in vitro growth, cell cycle G0/G1 arrest, and induced apoptosis in gastric cancer cells [2].
• Recent studies have demonstrated that BR binding to the extracellular domain of BRI1 induces kinase activation and dimerization with another receptor kinase, BAK1 [13].

Anatomical context of BAK1

• How cells maintain the potentially lethal proapoptotic effector BAK in a monomeric inactive conformation at mitochondria is unknown [14].
• It has been reported that gastric tumors have reduced BAK levels when compared with the normal mucosa [2].
• Our data indicate that transfection of dendritic cells with BAK/BAX siRNA represents a plausible strategy for enhancing dendritic cell-based vaccine potency [15].
• BCL-2, BAX and BAK localize also to the endoplasmic reticulum (ER), the main intracellular Ca(2+) store [16].
• While T-lymphocytes showed a regular BAK-staining, the other leukocytes were negative [17].

Associations of BAK1 with chemical compounds

• Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK [12].
• However, in contrast to 5-FU, mithramycin A failed to activate p53 target genes including the cell cycle inhibitor p21Cip1 gene as well as the proapoptotic genes PUMA (p53-upregulated mediator of apotosis) and BAK (bcl2-homologous antagonist/killer) and blocked the induction of the above genes by 5-FU [18].
• Despite the high spinning speeds employed during HRMAS (1)H NMR spectroscopy of one-half of the tumor samples, RT-PCR analysis of the pro-apoptotic transcripts Bcl-2, BAK-1, caspase-9 and FAS was possible, producing similar results to those detected in the unspun half of the tumors [19].
• RESULTS: PS-341 decreased BCL-2, without effect on BAX or BAK [20].
• Apoptosis inhibitors, i.e., IGFR type I and II were over-expressed, and apoptosis inducer, i.e., caspase 3 and BAK were underexpressed in highly cisplatin-resistant cell line, KFrP200 as compared to KFr [21].

Physical interactions of BAK1

• BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization [22].

Regulatory relationships of BAK1

• This model suggests that the primary mechanism for BCL-2 blockade targets activated BAK rather than sequestering tBID [22].
• Reversibly, overexpression of NOXA or PUMA induces apoptosis as evidenced by the activation of BAK and caspase-7 [23].

Other interactions of BAK1

• Our results indicate that 4ICD is functionally similar to BH3-only proteins, proapoptotic members of the BCL-2 family required for initiation of mitochondrial dysfunction through activation of the proapoptotic multi-BH domain proteins BAX/BAK [24].
• However, BCL-Xs and BAK were weakly expressed in K562, as were Bcl-X, BAD and BAK in the VAL line [25].
• BAK overexpression mediates p53-independent apoptosis inducing effects on human gastric cancer cells [2].
• Activated BRI1 or BAK1 then regulate, possibly indirectly, the activities of BIN2 kinase and/or BSU1 phosphatase, which directly regulate the phosphorylation status and nuclear accumulation of two homologous transcription factors, BZR1 and BES1 [13].
• We first show that PrP is very specific for Bax and cannot prevent Bak (Bcl-2 antagonist killer 1)-, tBid-, staurosporine- or thapsigargin-mediated cell death [26].

Analytical, diagnostic and therapeutic context of BAK1

• Immunohistochemistry for Bcl-2 antagonist/killer (Bak) was performed [27].
• More importantly, we found that vaccination with E7-loaded DCs transfected with BAK/BAX siRNA was capable of generating a strong therapeutic effect in vaccinated mice, compared with DCs transfected with control siRNA [15].
• Over-expression of p53/BAK in aseptic loosening after total hip replacement [17].
• Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy [28].
• Analysis by cDNA microarray and subsequent functional studies revealed that EGR2 directly transactivates expression of BNIP3L and BAK [29].

References