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Special Issue "Advances in Bcl-xL Research 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2021).

Special Issue Editor

Dr. Muriel Priault
E-Mail Website
Guest Editor
UMR CNRS 5095, I.B.G.C, Université de Bordeaux, 1 Rue Camille Saint Saëns, 33077 Bordeaux CEDEX, France
Interests: survival; aging; apoptosis; tumorigenesis; autophagy; deamidation; membrane protein structure
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Special Issue Information

Dear Colleagues,

The oncogene Bcl-xL is an anti-apoptotic member of the Bcl-2 family that was established as a major survival factor in erythroid lineage and neuronal cells. More recently, Bcl-xL also emerged as being responsible for the resistance of malignant tumor cells to anti-cancer treatments. Over the last decade, refined description of its regulation revealed that several mechanisms are at work that make Bcl-xL instrumental in the control of survival, proliferation, and differentiation. These mechanisms comprise post-translational modifications, the dynamic interactions this protein establishes with its target membranes, and also its interactions with binding partners within and outside the Bcl-2 family of proteins. This Special Issue of IJMS will focus on how Bcl-xL is regulated at the protein level, its organization in the membrane, the plasticity of its interactome, and how it warrants a diversity of cellular functions controlled by Bcl-xL in physiology and pathology. Articles submitted can either provide a review of specific points of the literature, or be original works offering significant advances in the structure and functions of Bcl-xL.

Dr. Muriel Priault
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Survival, proliferation, and differentiation
  • Mechanisms of tumor progression
  • Mitochondria/endoplasmic reticulum interplay
  • Membrane insertion/protein oligomerization
  • Targeted drug design

Published Papers (7 papers)

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Research

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Article
Effects of Cardiolipin on the Conformational Dynamics of Membrane-Anchored Bcl-xL
Int. J. Mol. Sci. 2021, 22(17), 9388; https://doi.org/10.3390/ijms22179388 - 30 Aug 2021
Cited by 1 | Viewed by 405
Abstract
The anti-apoptotic protein Bcl-xL regulates apoptosis by preventing the permeation of the mitochondrial outer membrane by pro-apoptotic pore-forming proteins, which release apoptotic factors into the cytosol that ultimately lead to cell death. Two different membrane-integrated Bcl-xL constructs have been identified: a membrane-anchored and [...] Read more.
The anti-apoptotic protein Bcl-xL regulates apoptosis by preventing the permeation of the mitochondrial outer membrane by pro-apoptotic pore-forming proteins, which release apoptotic factors into the cytosol that ultimately lead to cell death. Two different membrane-integrated Bcl-xL constructs have been identified: a membrane-anchored and a membrane-inserted conformation. Here, we use molecular dynamics simulations to study the effect of the mitochondrial specific lipid cardiolipin and the protein protonation state on the conformational dynamics of membrane-anchored Bcl-xL. The analysis reveals that the protonation state of the protein and cardiolipin content of the membrane modulate the orientation of the soluble head region (helices α1 through α7) and hence the exposure of its BH3-binding groove, which is required for its interaction with pro-apoptotic proteins. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research 2.0)
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Article
BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response
Int. J. Mol. Sci. 2021, 22(8), 3811; https://doi.org/10.3390/ijms22083811 - 07 Apr 2021
Cited by 1 | Viewed by 564
Abstract
Colorectal cancer (CRC) is a heterogeneous disease, which in part explains the differential response to chemotherapy observed in the clinic. BH3 mimetics, which target anti-apoptotic BCL-2 family members, have shown potential in the treatment of hematological malignancies and offer promise for the treatment [...] Read more.
Colorectal cancer (CRC) is a heterogeneous disease, which in part explains the differential response to chemotherapy observed in the clinic. BH3 mimetics, which target anti-apoptotic BCL-2 family members, have shown potential in the treatment of hematological malignancies and offer promise for the treatment of solid tumors as well. To gain a comprehensive understanding of the response to BH3 mimetics in CRC and the underlying molecular factors predicting sensitivity, we screened a panel of CRC cell lines with four BH3 mimetics targeting distinct anti-apoptotic BCL-2 proteins. Treatment with compounds alone and in combination revealed potent efficacy of combined MCL-1 and BCL-XL inhibition in inducing CRC cell death, irrespective of molecular features. Importantly, expression of the anti-apoptotic protein target of BH3 mimetics on its own did not predict sensitivity. However, the analysis did identify consensus molecular subtype (CMS) specific response patterns, such as higher resistance to single and combined BCL-2 and MCL-1 inhibition in CMS2 cell lines. Furthermore, analysis of mutation status revealed that KRAS mutant cell lines were more resistant to MCL-1 inhibition. Conclusively, we find that CRC cell lines presented with distinct responses to BH3 mimetics that can in part be predicted by their CMS profile and KRAS/BRAF mutations. Overall, almost all CRC lines share sensitivity in the nanomolar range to combined MCL-1 and BCL-XL targeting suggesting that this would be the preferred approach to target these cancers. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research 2.0)
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Review

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Review
Bcl-2 Modulation in p53 Signaling Pathway by Flavonoids: A Potential Strategy towards the Treatment of Cancer
Int. J. Mol. Sci. 2021, 22(21), 11315; https://doi.org/10.3390/ijms222111315 - 20 Oct 2021
Viewed by 404
Abstract
Cancer is a major cause of death, affecting human life in both developed and developing countries. Numerous antitumor agents exist but their toxicity and low efficacy limits their utility. Furthermore, the complex pathophysiological mechanisms of cancer, serious side effects and poor prognosis restrict [...] Read more.
Cancer is a major cause of death, affecting human life in both developed and developing countries. Numerous antitumor agents exist but their toxicity and low efficacy limits their utility. Furthermore, the complex pathophysiological mechanisms of cancer, serious side effects and poor prognosis restrict the administration of available cancer therapies. Thus, developing novel therapeutic agents are required towards a simultaneous targeting of major dysregulated signaling mediators in cancer etiology, while possessing lower side effects. In this line, the plant kingdom is introduced as a rich source of active phytochemicals. The secondary metabolites produced by plants could potentially regulate several dysregulated pathways in cancer. Among the secondary metabolites, flavonoids are hopeful phytochemicals with established biological activities and minimal side effects. Flavonoids inhibit B-cell lymphoma 2 (Bcl-2) via the p53 signaling pathway, which is a significant apoptotic target in many cancer types, hence suppressing a major dysregulated pathway in cancer. To date, there have been no studies reported which extensively highlight the role of flavonoids and especially the different classes of flavonoids in the modulation of Bcl-2 in the P53 signaling pathway. Herein, we discuss the modulation of Bcl-2 in the p53 signaling pathway by different classes of flavonoids and highlight different mechanisms through which this modulation can occur. This study will provide a rationale for the use of flavonoids against different cancers paving a new mechanistic-based approach to cancer therapy. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research 2.0)
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Review
Involvement of Bcl-xL in Neuronal Function and Development
Int. J. Mol. Sci. 2021, 22(6), 3202; https://doi.org/10.3390/ijms22063202 - 21 Mar 2021
Viewed by 883
Abstract
The B-cell lymphoma (Bcl-2) family of proteins are mainly known for their role in the regulation of apoptosis by preventing pore formation at the mitochondrial outer membrane and subsequent caspase activation. However, Bcl-2 proteins also have non-canonical functions, independent of apoptosis. Indeed, the [...] Read more.
The B-cell lymphoma (Bcl-2) family of proteins are mainly known for their role in the regulation of apoptosis by preventing pore formation at the mitochondrial outer membrane and subsequent caspase activation. However, Bcl-2 proteins also have non-canonical functions, independent of apoptosis. Indeed, the cell death machinery, including Bcl-2 homologs, was reported to be essential for the central nervous system (CNS), notably with respect to synaptic transmission and axon pruning. Here we focused on Bcl-xL, a close Bcl-2 homolog, which plays a major role in neuronal development, as bclx knock out mice prematurely die at embryonic day 13.5, showing massive apoptosis in the CNS. In addition, we present evidence that Bcl-xL fosters ATP generation by the mitochondria to fuel high energy needs by neurons, and its contribution to synaptic transmission. We discuss how Bcl-xL might control local and transient activation of caspases in neurons without causing cell death. Consistently, Bcl-xL may contribute to morphological changes, such as sprouting and retractation of axon branches, in the context of CNS plasticity. Regarding degenerative diseases and aging, a better understanding of the numerous roles of the cell death machinery in neurons may have future clinical implications. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research 2.0)
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Review
Bcl-xL: A Focus on Melanoma Pathobiology
Int. J. Mol. Sci. 2021, 22(5), 2777; https://doi.org/10.3390/ijms22052777 - 09 Mar 2021
Viewed by 1156
Abstract
Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and pro-apoptotic proteins is necessary in order to avoid impaired apoptosis, which is the cause of several pathologies, including cancer. Among [...] Read more.
Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and pro-apoptotic proteins is necessary in order to avoid impaired apoptosis, which is the cause of several pathologies, including cancer. Among the anti-apoptotic proteins, Bcl-xL exhibits a high conformational flexibility, whose regulation is strictly controlled by alternative splicing and post-transcriptional regulation mediated by transcription factors or microRNAs. It shows relevant functions in different forms of cancer, including melanoma. In melanoma, Bcl-xL contributes to both canonical roles, such as pro-survival, protection from apoptosis and induction of drug resistance, and non-canonical functions, including promotion of cell migration and invasion, and angiogenesis. Growing evidence indicates that Bcl-xL inhibition can be helpful for cancer patients, but at present, effective and safe therapies targeting Bcl-xL are lacking due to toxicity to platelets. In this review, we summarized findings describing the mechanisms of Bcl-xL regulation, and the role that Bcl-xL plays in melanoma pathobiology and response to therapy. From these findings, it emerged that even if Bcl-xL plays a crucial role in melanoma pathobiology, we need further studies aimed at evaluating the involvement of Bcl-xL and other members of the Bcl-2 family in the progression of melanoma and at identifying new non-toxic Bcl-xL inhibitors. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research 2.0)
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Review
The Role of Bcl-xL Protein in Viral Infections
Int. J. Mol. Sci. 2021, 22(4), 1956; https://doi.org/10.3390/ijms22041956 - 16 Feb 2021
Cited by 2 | Viewed by 780
Abstract
Bcl-xL represents a family of proteins responsible for the regulation of the intrinsic apoptosis pathway. Due to its anti-apoptotic activity, Bcl-xL co-determines the viability of various virally infected cells. Their survival may determine the effectiveness of viral replication and spread, dynamics of systemic [...] Read more.
Bcl-xL represents a family of proteins responsible for the regulation of the intrinsic apoptosis pathway. Due to its anti-apoptotic activity, Bcl-xL co-determines the viability of various virally infected cells. Their survival may determine the effectiveness of viral replication and spread, dynamics of systemic infection, and viral pathogenesis. In this paper, we have reviewed the role of Bcl-xL in the context of host infection by eight different RNA and DNA viruses: hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), influenza A virus (IAV), Epstein-Barr virus (EBV), human T-lymphotropic virus type-1 (HTLV-1), Maraba virus (MRBV), Schmallenberg virus (SBV) and coronavirus (CoV). We have described an influence of viral infection on the intracellular level of Bcl-xL and discussed the impact of Bcl-xL-dependent cell survival control on infection-accompanying pathogenic events such as tissue damage or oncogenesis. We have also presented anti-viral treatment strategies based on the pharmacological regulation of Bcl-xL expression or activity. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research 2.0)
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Review
Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases
Int. J. Mol. Sci. 2020, 21(20), 7591; https://doi.org/10.3390/ijms21207591 - 14 Oct 2020
Cited by 2 | Viewed by 899
Abstract
Blood platelets have important roles in haemostasis, where they quickly stop bleeding in response to vascular damage. They have also recognised functions in thrombosis, immunity, antimicrobal defense, cancer growth and metastasis, tumour angiogenesis, lymphangiogenesis, inflammatory diseases, wound healing, liver regeneration and neurodegeneration. Their [...] Read more.
Blood platelets have important roles in haemostasis, where they quickly stop bleeding in response to vascular damage. They have also recognised functions in thrombosis, immunity, antimicrobal defense, cancer growth and metastasis, tumour angiogenesis, lymphangiogenesis, inflammatory diseases, wound healing, liver regeneration and neurodegeneration. Their brief life span in circulation is strictly controlled by intrinsic apoptosis, where the prosurvival Bcl-2 family protein, Bcl-xL, has a major role. Blood platelets are produced by large polyploid precursor cells, megakaryocytes, residing mainly in the bone marrow. Together with Mcl-1, Bcl-xL regulates megakaryocyte survival. This review describes megakaryocyte maturation and survival, platelet production, platelet life span and diseases of abnormal platelet number with a focus on the role of Bcl-xL during these processes. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research 2.0)
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