Abstract:Bok is a member of the Bcl-2 protein family that governs the intrinsic apoptosis pathway, although the role that Bok plays in this pathway is unclear. We have shown previously in cultured cell lines that Bok interacts strongly with inositol 1,4,5-trisphosphate receptors (IP 3 Rs), suggesting that it may contribute to the structural integrity or stability of IP 3 R tetramers. Here we report that Bok is similarly IP 3 R-assocated in mouse tissues, that essentially all cellular Bok is IP 3 R bound, that it is the… Show more
“…BOK has been shown to interact with IP3 receptors, protecting IP3Rs from caspase‐mediated degradation and BOK from proteasomal degradation . Degradation of BOK via the ubiquitin/proteasome was also shown by Llambi et al .…”
The BCL-2 family members are key regulators of the intrinsic apoptotic pathway, which is defined by permeabilization of the mitochondrial outer membrane by members of the BAX-like subfamily. BOK is classified as a BAX-like protein; however, its (patho-)physiological role remains largely unclear. We therefore assessed the membrane permeabilization potential of C-terminally truncated recombinant BOK, BOK ΔC . We show that BOK ΔC can permeabilize liposomes mimicking the composition of mitochondrial outer membrane, but not of endoplasmic reticulum, forming large and stable pores over time. Importantly, pore formation was enhanced by the presence of cBID and refractory to the addition of antiapoptotic BCL-X L . However, isolated mitochondria from Bax À/À Bak À/À cells were resistant to BOK-induced cytochrome c release, even in the presence of cBID. Taken together, we show that BOK ΔC can permeabilize liposomes, and cooperate with cBID, but its role in directly mediating mitochondrial permeabilization is unclear and may underlie a yet to be determined negative regulation.
“…BOK has been shown to interact with IP3 receptors, protecting IP3Rs from caspase‐mediated degradation and BOK from proteasomal degradation . Degradation of BOK via the ubiquitin/proteasome was also shown by Llambi et al .…”
The BCL-2 family members are key regulators of the intrinsic apoptotic pathway, which is defined by permeabilization of the mitochondrial outer membrane by members of the BAX-like subfamily. BOK is classified as a BAX-like protein; however, its (patho-)physiological role remains largely unclear. We therefore assessed the membrane permeabilization potential of C-terminally truncated recombinant BOK, BOK ΔC . We show that BOK ΔC can permeabilize liposomes mimicking the composition of mitochondrial outer membrane, but not of endoplasmic reticulum, forming large and stable pores over time. Importantly, pore formation was enhanced by the presence of cBID and refractory to the addition of antiapoptotic BCL-X L . However, isolated mitochondria from Bax À/À Bak À/À cells were resistant to BOK-induced cytochrome c release, even in the presence of cBID. Taken together, we show that BOK ΔC can permeabilize liposomes, and cooperate with cBID, but its role in directly mediating mitochondrial permeabilization is unclear and may underlie a yet to be determined negative regulation.
“…Consistent with this interpretation, BOK inhibited TGF-β2-induced cell migration, as assessed by Boyden chamber migration assay (Figure 5c). Furthermore, we detected TGFβ2-induced increase of ATF4 as well as a shorter form of BOK that lacks the N-terminus due to alternative translation initiation at Met 15 (13); ATF4, being required for cell invasion (24), was slightly diminished in TGFβ2-treated cell upon additional BOK overexpression and was accompanied by reduction of the shorter form of BOK (Figure 5e). …”
Section: Resultsmentioning
confidence: 99%
“…Importantly, we found that BOK levels were significantly decreased in tumors of lymph node positive patients and in less differentiated tumors compared to adjacent lung parenchyma (Figure 1b). This phenotype might be favoured by epigenetic mechanisms during tumor progression (Figure 3, 33) and/or by proteasome-dependent regulation of BOK levels (1, 13). Importantly, we found a poor correlation between BOK mRNA and protein levels.…”
Section: Discussionmentioning
confidence: 99%
“…Even though it is known that overexpressed BOK leads to the release of cytochrome-c from mitochondria leading to procaspase-9 activation, exact mechanisms of this pro-death function are controversially discussed as is its pro-apoptotic function under physiological conditions (1, 2, 5–10). Intriguingly, most of the cytoplasmic BOK seems to be localized at the endoplasmic reticulum (2, 11, 12), by a mechanism requiring its C-terminal tail-anchor (2), where it strongly interacts with IP3 receptors and is subject to posttranslational regulation through ubiquitination and proteasomal degradation (1, 13, 14). Significant amounts of BOK are also found within the nuclear compartment (2, 11) and non-apoptotic roles in regulation of proliferation (12), and even protective roles in response to specific stressors or in specialized cell types have been proposed (2, 15).…”
Since the genomic region containing the Bcl-2-related ovarian killer (BOK) locus is frequently deleted in certain human cancers, BOK is hypothesized to have a tumor suppressor function. In the present study, we analyzed primary non-small cell lung carcinoma (NSCLC) tumors and matched lung tissues from 102 surgically treated patients. We show that BOK protein levels are significantly downregulated in NSCLC tumors as compared to lung tissues (P<0.001). In particular, we found BOK downregulation in NSCLC tumors of grades two (P=0.004, n=35) and three (P=0.031, n=39) as well as in tumors with metastases to hilar (pN1) (P=0.047, n=31) and mediastinal/subcarinal lymph nodes (pN2) (P=0.021, n=18) as opposed to grade one tumors (P=0.688, n=7) and tumors without lymph node metastases (P=0.112, n=51). Importantly, in lymph node positive patients, BOK expression greater than the median value was associated with longer survival (P=0.002, Mantel test). Using in vitro approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGFβ-induced migration and epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma-derived A549 cells. We have identified epigenetic mechanisms, in particular BOK promoter methylation, as an important means to silence BOK expression in NSCLC cells. Taken together, our data point toward a novel mechanism by which BOK acts as a tumor suppressor in NSCLC by inhibiting EMT. Consequently, the restoration of BOK levels in low-BOK-expressing tumors might favor the overall survival of NSCLC patients.
“…Recent evidence has indicated that Bok interacts strongly with IP3Rs and may contribute to the structural integrity or stability of IP3R tetramers (Schulman et al 2013). In return, Bok is dramatically stabilized by binding to IP3Rs and the proapoptotic effects of overexpressed Bok could be limited (Schulman et al 2016). PKB/Akt, which is a well-known prosurvival factor, exerts critical neuroprotective effects by phosphorylating downstream targets after TBI.…”
The endoplasmic reticulum (ER) and mitochondria have both been shown to be critical in cellular homeostasis. The functions of the ER and mitochondria are independent but interrelated. These two organelles could form physical interactions, known as MAMs, to regulate physiological functions between ER and mitochondria to maintain Ca, lipid, and metabolite exchange. Several proteins are located in MAMs, including RNA-dependent protein kinase (PKR)-like ER kinase, inositol 1,4,5-trisphosphate receptors, phosphofurin acidic cluster sorting protein-2 and sigma-1 receptor to ensure regulation. Recent studies indicated that MAMs participate in inflammation and apoptosis in various conditions. All of these functions are crucial in determining cell fate following traumatic brain injury (TBI). We hypothesized that MAMs may associate with TBI and could contribute to mitochondrial dysfunction, ER stress, autophagy dysregulation, dysregulation of Ca homeostasis, and oxidative stress. In this review, we summarize the latest understanding of MAM formation and their potential regulatory role in TBI pathophysiology.
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