Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak

Einsele‐Scholz, Stephanie; Malmsheimer, Silke; Bertram, Katrin; Stehle, Daniel; Johänning, Janina; Manz, Marianne; Daniel, Peter T.; Gillissen, Bernhard; Schulze‐Osthoff, Klaus; Eßmann, Frank

doi:10.1242/jcs.181727

Cited by 48 publications

(30 citation statements)

References 41 publications

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“…Similar to ATG4B, BOK is also down‐regulated in lesional skin of patients with AA. BOK is a pro‐apoptotic member of the BCL2 family that also induces autophagy . Therefore, it is possible that in patients with AA the tandem deletion of ATG4B and BOK could result in an additive effect in which multiple autophagy genes are perturbed, causing a more pronounced deficit in the pathway.…”

Section: Discussionmentioning

confidence: 99%

“…BOK is a pro-apoptotic member of the BCL2 family that also induces autophagy. [66,67] Therefore, it is possible that in patients with AA the tandem deletion of ATG4B and BOK could result in an additive effect in which multiple autophagy genes are perturbed, causing a more pronounced deficit in the pathway. Future studies are needed to further refine contributions from BOK.…”

Section: Discussionmentioning

confidence: 99%

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Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

Petukhova

Patel

Rigo

et al. 2019

Experimental Dermatology

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Alopecia areata (AA) is a highly prevalent autoimmune disease that attacks the hair follicle and leads to hair loss that can range from small patches to complete loss of scalp and body hair. Our previous linkage and genome‐wide association studies (GWAS) generated strong evidence for aetiological contributions from inherited genetic variants at different population frequencies, including both rare mutations and common polymorphisms. Additionally, we conducted gene expression (GE) studies on scalp biopsies of 96 patients and controls to establish signatures of active disease. In this study, we performed an integrative analysis on these two datasets to test the hypothesis that rare CNVs in patients with AA could be leveraged to identify drivers of disease in our AA GE signatures. We analysed copy number variants (CNVs) in a case‐control cohort of 673 patients with AA and 16 311 controls independent of the case‐control cohort of 96 research participants used in our GE study. Using an integrative computational analysis, we identified 14 genes whose expression levels were altered by CNVs in a consistent direction of effect, corresponding to gene expression changes in lesional skin of patients. Four of these genes were affected by CNVs in three or more unrelated patients with AA, including ATG4B and SMARCA2, which are involved in autophagy and chromatin remodelling, respectively. Our findings identified new classes of genes with potential contributions to AA pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

Petukhova

Patel

Rigo

et al. 2019

Experimental Dermatology

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“…Accordingly, BOK was shown to have proapoptotic function upon overexpression (1–4). 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).…”

Section: Introductionmentioning

confidence: 99%

BOK displays cell death‐independent tumor suppressor activity in non‐small‐cell lung carcinoma

Moravcikova

Kr̆epela

Donnenberg

et al. 2017

Intl Journal of Cancer

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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.

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“…2). Among these, Bim, Bad, Puma, Bid, Bik, Bmf, Hrk and Noxa have a BH3-only domain [21]; and Bax, Bak, and Bok have multiple domains (BH1–3) [22]. Antiapoptotic regulators of the Bcl-2 family include Bcl-2, Bcl-XL, Bcl-w, and Mcl-1 [23].…”

Section: Apoptosis and Its Regulatorsmentioning

confidence: 99%

“…Proapoptotic Bok is persistently active without apparent regulators except Mcl-1 [26]. It is proposed that Bok is regulated at expression levels through ER-associated degradation pathways [22,27]. …”

Section: Apoptosis and Its Regulatorsmentioning

confidence: 99%

TMBIM-mediated Ca2+ homeostasis and cell death

Liu

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Ca2+ is a ubiquitous intracellular messenger that regulates numerous physiological activities in humans, animals, plants, and bacteria. Cytosolic Ca2+ is kept at a low level, but subcellular organelles such as the endoplasmic reticulum (ER) and Golgi apparatus maintain high-concentration Ca2+ stores. Under resting conditions, store Ca2+ homeostasis is dynamically regulated to equilibrate between active Ca2+ uptake and passive Ca2+ leak processes. The evolutionarily conserved Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) proteins mediate Ca2+ homeostasis and cell death. This review focuses on recent advances in functional and structural analysis of TMBIM proteins in regulation of the two related functions. The roles of TMBIM proteins in pathogen infection and cancer are also discussed with prospects for treatment.

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Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak

Cited by 48 publications

References 41 publications

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an aetiological role for autophagy

BOK displays cell death‐independent tumor suppressor activity in non‐small‐cell lung carcinoma

TMBIM-mediated Ca2+ homeostasis and cell death

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