Structural insights into apoptotic regulation of human Bfk as a novel Bcl-2 family member

Jang, Dong Man; Oh, Eunyoung; Hahn, Hyunggu; Kim, Hyoun Sook; Han, Byung Woo

doi:10.1016/j.csbj.2022.01.023

Cited by 4 publications

(6 citation statements)

References 58 publications

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“…These data suggest that positively selected and rapidly evolving genes have contributed to the divergence of cell death pathways in elephants. Among the rapidly evolving genes, for example, is CASP8 , the initiator caspase of extrinsic apoptosis, necroptosis, and pyroptosis (Boldin et al, 1996; Fritsch et al, 2019; Muzio et al, 1996), APAF1 , which forms the central scaffold of the apoptosome and and thus plays a critical role in apoptosis (Bratton and Salvesen, 2010; Cain et al, 2002), BOK an unusual BCL-2 family protein that directly induces mitochondrial outer membrane permeabilization (MOMP) and apoptosis in response to endoplasmic reticulum (ER) stress (Carpio et al, 2015; Llambi et al, 2016), BCL2L15 , another unusual BCL-2 family protein with pro-apoptotic functions that reduces malignant transformation of cells in the gastrointestinal tract (Dempsey et al, 2005; Jang et al, 2022; Özören et al, 2009) , BCLAP a tumor suppressor that induces cell cycle arrest at the G 1 /S and apoptosis through an uncharacterized but p53-independent mechanisms (Fan et al, 2011; Han et al, 2022; Yao et al, 2007; ZHAO et al, 2016), KDM6B , which promotes parthanatos by inhibiting DNA damage-evoked PARP-1 hyperactivation (Yang et al, 2022), and ALKBH7 is required for alkylation and oxidation-induced programmed necrosis (Fu et al, 2013; Jordan et al, 2017; Kulkarni et al, 2020). Remarkably, other cancer-resistant species have also evolved modified cell death pathways.…”

Section: Discussionmentioning

confidence: 99%

Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants

Bowman,

Lynch

2024

Preprint

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Elephants have emerged as a model system to study the evolution of body size and cancer resistance because, despite their immense size, they have a very low prevalence of cancer. Previous studies have found that duplication of tumor suppressors at least partly contributes to the evolution of anti-cancer cellular phenotypes in elephants. Still, many other mechanisms must have contributed to their augmented cancer resistance. Here, we use a suite of codon-based maximum-likelihood methods and a dataset of 13,310 protein-coding gene alignments from 261 Eutherian mammals to identify positively selected and rapidly evolving elephant genes. We found 496 genes (3.73% of alignments tested) with statistically significant evidence for positive selection and 660 genes (4.96% of alignments tested) that likely evolved rapidly in elephants. Positively selected and rapidly evolving genes are statistically enriched in gene ontology terms and biological pathways related to regulated cell death mechanisms, DNA damage repair, cell cycle regulation, epidermal growth factor receptor (EGFR) signaling, and immune functions, particularly neutrophil granules and degranulation. All of these biological factors are plausibly related to the evolution of cancer resistance. Thus, these positively selected and rapidly evolving genes are promising candidates for genes contributing to elephant-specific traits, including the evolution of molecular and cellular characteristics that enhance cancer resistance.

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Section: Discussionmentioning

confidence: 99%

Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants

Bowman,

Lynch

2024

Preprint

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“…In this respect, BCL-2 family Kin (BFK) is another example of a BCL-2like protein, which is structurally similar to BCL-G L [112]. A recently published report on BFK might shed light on the directions of further research on BCL-G [113]. Biophysical interaction analysis revealed that full-length BFK did not interact with other BCL-2-like Fig.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…In this respect, BCL-2 family Kin (BFK) is another example of a BCL-2-like protein, which is structurally similar to BCL-G L [ 112 ]. A recently published report on BFK might shed light on the directions of further research on BCL-G [ 113 ]. Biophysical interaction analysis revealed that full-length BFK did not interact with other BCL-2-like proteins, but instead it was functionally reminiscent of BID, in which the BH3 domain was released upon caspase-mediated cleavage and truncated form (tBID) underwent a conformational alteration [ 113 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…A recently published report on BFK might shed light on the directions of further research on BCL-G [ 113 ]. Biophysical interaction analysis revealed that full-length BFK did not interact with other BCL-2-like proteins, but instead it was functionally reminiscent of BID, in which the BH3 domain was released upon caspase-mediated cleavage and truncated form (tBID) underwent a conformational alteration [ 113 ]. In addition, as protein modifications with ubiquitin-like moieties were shown to regulate the activity of target proteins, their intracellular localization and interactions with other proteins [ 114 ], the activity of FAU via BCL-G should be taken into account when the role of BCL-G is identified.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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BCL-G: 20 years of research on a non-typical protein from the BCL-2 family

Hartman

Czyż

2023

Cell Death Differ

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Proteins from the BCL-2 family control cell survival and apoptosis in health and disease, and regulate apoptosis-unrelated cellular processes. BCL-Gonad (BCL-G, also known as BCL2-like 14) is a non-typical protein of the family as its long isoform (BCL-GL) consists of BH2 and BH3 domains without the BH1 motif. BCL-G is predominantly expressed in normal testes and different organs of the gastrointestinal tract. The complexity of regulatory mechanisms of BCL-G expression and post-translational modifications suggests that BCL-G may play distinct roles in different types of cells and disorders. While several genetic alterations of BCL2L14 have been reported, gene deletions and amplifications prevail, which is also confirmed by the analysis of sequencing data for different types of cancer. Although the studies validating the phenotypic consequences of genetic manipulations of BCL-G are limited, the role of BCL-G in apoptosis has been undermined. Recent studies using gene-perturbation approaches have revealed apoptosis-unrelated functions of BCL-G in intracellular trafficking, immunomodulation, and regulation of the mucin scaffolding network. These studies were, however, limited mainly to the role of BCL-G in the gastrointestinal tract. Therefore, further efforts using state-of-the-art methods and various types of cells are required to find out more about BCL-G activities. Deciphering the isoform-specific functions of BCL-G and the BCL-G interactome may result in the designing of novel therapeutic approaches, in which BCL-G activity will be either imitated using small-molecule BH3 mimetics or inhibited to counteract BCL-G upregulation. This review summarizes two decades of research on BCL-G.

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“…In addition to their traditional function of suppressing apoptosis, BCL-2 and BCL-XL have been shown to have a role in the regulation of other critical cellular processes, including proliferation, autophagy, differentiation, DNA repair, tumor growth, and angiogenesis via their BH4 domain [21]. The antiapoptotic and proapoptotic proteins contain four BH domains which take on a conserved functional group containing six or seven amphiphilic a-helices and two hydrophobic a-helices at the center to form a hydrophobic BH3 domain-binding cleft that works as a receptor for BH3 domains [17,22]. These four BH domain-containing (BH1-BH4) proteins inhibit apoptosis by interacting and trapping their pro-apoptotic counterparts [23].…”

Section: Introductionmentioning

confidence: 99%

Emerging biomarkers and potential therapeutics of the BCL-2 protein family: the apoptotic and anti-apoptotic context

Saddam,

Paul,

Habib

et al. 2024

Egypt J Med Hum Genet

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Apoptosis, also known as the programmed death of cells, is responsible for maintaining the homeostasis of tissues, and this function is carried out by caspases. The process of apoptosis is carried out via two distinct pathways: the extrinsic pathway, which is governed by death receptors, and the intrinsic pathway, also known as the mitochondrial pathway. The BCL-2 protein family encoded by the BCL-2 gene, located at the 18q21.33 chromosomal location, is in charge of regulating the intrinsic pathway, which is responsible for inducing cell death via the permeabilization of the mitochondrial membrane and the release of apoptosis-inducing components. The BCL-2 homology (BH1, BH2, BH3, BH4) domains of this family proteins are crucial for their functioning, and their common BH domains allow interactions between members of the same family and can also serve as indications of pro- or anti-apoptotic activity. A direct correlation may be shown between the overexpression of BCL-2 and the postponement of cell death. It has been determined that a change in the expression of BCL-2 is the root cause of a variety of malignancies, including lung, breast, melanoma, and chronic lymphocytic leukemia, multiple sclerosis, diabetes. In this review, we addressed the genetic information and structural homology of BCL-2 family members. Further, we elucidate the pro-apoptotic and anti-apoptotic roles of the family members. This review highlights the most recent developments in the BCL-2 protein family and presents evidence that targeting this family proteins may have a positive impact on the treatment of medical problems that are still underserved.

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Structural insights into apoptotic regulation of human Bfk as a novel Bcl-2 family member

Abstract: Graphical abstract

Cited by 4 publications

References 58 publications

Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants

Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants

BCL-G: 20 years of research on a non-typical protein from the BCL-2 family

Emerging biomarkers and potential therapeutics of the BCL-2 protein family: the apoptotic and anti-apoptotic context

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