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Advances in Bcl-xL Research

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 (31 October 2019) | Viewed by 20900

Special Issue 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

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Keywords

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

Published Papers (5 papers)

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Research

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17 pages, 4072 KiB  
Article
Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons
by Han-A Park, Nelli Mnatsakanyan, Katheryn Broman, Abigail U. Davis, Jordan May, Pawel Licznerski, Kristi M. Crowe-White, Kimberly H. Lackey and Elizabeth A. Jonas
Int. J. Mol. Sci. 2020, 21(1), 220; https://doi.org/10.3390/ijms21010220 - 28 Dec 2019
Cited by 18 | Viewed by 3859
Abstract
B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumulation of ∆N-Bcl-xL causes mitochondrial dysfunction and neuronal [...] Read more.
B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumulation of ∆N-Bcl-xL causes mitochondrial dysfunction and neuronal death. In this study, we hypothesized that the generation of reactive oxygen species (ROS) during excitotoxicity leads to formation of ∆N-Bcl-xL. We further proposed that the application of an antioxidant with neuroprotective properties such as α-tocotrienol (TCT) will prevent ∆N-Bcl-xL-induced mitochondrial dysfunction via its antioxidant properties. Primary hippocampal neurons were treated with α-TCT, glutamate, or a combination of both. Glutamate challenge significantly increased cytosolic and mitochondrial ROS and ∆N-Bcl-xL levels. ∆N-Bcl-xL accumulation was accompanied by intracellular ATP depletion, loss of mitochondrial membrane potential, and cell death. α-TCT prevented loss of mitochondrial membrane potential in hippocampal neurons overexpressing ∆N-Bcl-xL, suggesting that ∆N-Bcl-xL caused the loss of mitochondrial function under excitotoxic conditions. Our data suggest that production of ROS is an important cause of ∆N-Bcl-xL formation and that preventing ROS production may be an effective strategy to prevent ∆N-Bcl-xL-mediated mitochondrial dysfunction and thus promote neuronal survival. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research)
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9 pages, 1296 KiB  
Article
Improved Electrophoretic Separation to Assist the Monitoring of Bcl-xL Post-Translational Modifications
by Claude Bobo, Claire Céré, Mélody Dufossée, Alain Dautant, Violaine Moreau, Stéphen Manon, Florian Beaumatin and Muriel Priault
Int. J. Mol. Sci. 2019, 20(22), 5571; https://doi.org/10.3390/ijms20225571 - 08 Nov 2019
Cited by 10 | Viewed by 2861
Abstract
Bcl-xL is an oncogene of which the survival functions are finely tuned by post-translational modifications (PTM). Within the Bcl-2 family of proteins, Bcl-xL shows unique eligibility to deamidation, a time-related spontaneous reaction. Deamidation is still a largely overlooked PTM due to [...] Read more.
Bcl-xL is an oncogene of which the survival functions are finely tuned by post-translational modifications (PTM). Within the Bcl-2 family of proteins, Bcl-xL shows unique eligibility to deamidation, a time-related spontaneous reaction. Deamidation is still a largely overlooked PTM due to a lack of easy techniques to monitor Asn→Asp/IsoAsp conversions or Glu→Gln conversions. Being able to detect PTMs is essential to achieve a comprehensive description of all the regulatory mechanisms and functions a protein can carry out. Here, we report a gel composition improving the electrophoretic separation of deamidated forms of Bcl-xL generated either by mutagenesis or by alkaline treatment. Importantly, this new gel formulation proved efficient to provide the long-sought evidence that even doubly-deamidated Bcl-xL remains eligible for regulation by phosphorylation. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research)
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Review

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14 pages, 408 KiB  
Review
The Role of Bcl-xL Protein Research in Veterinary Oncology
by Aleksandra Pawlak and Marta Henklewska
Int. J. Mol. Sci. 2020, 21(7), 2511; https://doi.org/10.3390/ijms21072511 - 04 Apr 2020
Cited by 3 | Viewed by 2388
Abstract
Due to their significant impact on human and animal health, cancer diseases are an area of considerable concern for both human and veterinary medicine. Research on the cancer pathogenesis in companion animals, such as dogs, allows not only for improving canine cancer treatment, [...] Read more.
Due to their significant impact on human and animal health, cancer diseases are an area of considerable concern for both human and veterinary medicine. Research on the cancer pathogenesis in companion animals, such as dogs, allows not only for improving canine cancer treatment, but also for translating the results into human oncology. Disruption of apoptosis in tumor-transformed cells is a well-known mechanism leading to the development of cancer. One of the main factors involved in this process are proteins belonging to the B-cell lymphoma 2 (Bcl-2) family, and the imbalance between pro-apoptotic and anti-apoptotic members of this family contributes to the development of cancer. Studies on the function of these proteins, including B-cell lymphoma-extra large (Bcl-xL), have also been intensively conducted in companion animals. The Bcl-xL gene was sequenced and found to share over 99% homology with the human protein. Research showed that the Bcl-2 family plays the same role in human and canine cells, and data from studies in dogs are fully translatable to other species, including humans. The role of this protein family in cancer development was also confirmed. The article presents the current state of knowledge on the importance of the Bcl-xL protein in veterinary oncology. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research)
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13 pages, 2594 KiB  
Review
BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians
by Consuelo Borrás, Cristina Mas-Bargues, Aurora Román-Domínguez, Jorge Sanz-Ros, Lucia Gimeno-Mallench, Marta Inglés, Juan Gambini and José Viña
Int. J. Mol. Sci. 2020, 21(2), 418; https://doi.org/10.3390/ijms21020418 - 09 Jan 2020
Cited by 24 | Viewed by 5092
Abstract
B-Cell Lymphoma-extra-large (BCL-xL) is involved in longevity and successful aging, which indicates a role for BCL-xL in cell survival pathway regulation. Beyond its well described role as an inhibitor of apoptosis by preventing cytochrome c release, BCL-xL has also been related, indirectly, to [...] Read more.
B-Cell Lymphoma-extra-large (BCL-xL) is involved in longevity and successful aging, which indicates a role for BCL-xL in cell survival pathway regulation. Beyond its well described role as an inhibitor of apoptosis by preventing cytochrome c release, BCL-xL has also been related, indirectly, to autophagy and senescence pathways. Although in these latter cases, BCL-xL has dual roles, either activating or inhibiting, depending on the cell type and the specific conditions. Taken together, all these findings suggest a precise mechanism of action for BCL-xL, able to regulate the crosstalk between apoptosis, autophagy, and senescence, thus promoting cell survival or cell death. All three pathways can be both beneficial or detrimental depending on the circumstances. Thus, targeting BCL-xL would in turn be a “double-edge sword” and therefore, additional studies are needed to better comprehend this dual and apparently contradictory role of BCL-XL in longevity. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research)
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18 pages, 2595 KiB  
Review
The Structural Biology of Bcl-xL
by Erinna F. Lee and W. Douglas Fairlie
Int. J. Mol. Sci. 2019, 20(9), 2234; https://doi.org/10.3390/ijms20092234 - 07 May 2019
Cited by 41 | Viewed by 6276
Abstract
Interactions between the pro-survival and pro-apoptotic members of the Bcl-2 family of proteins dictate whether a cell lives or dies. Much of our knowledge of the molecular details of these interactions has come from biochemical and structural studies on the pro-survival protein Bcl-x [...] Read more.
Interactions between the pro-survival and pro-apoptotic members of the Bcl-2 family of proteins dictate whether a cell lives or dies. Much of our knowledge of the molecular details of these interactions has come from biochemical and structural studies on the pro-survival protein Bcl-xL. The first high-resolution structure of any Bcl-2 family member was of Bcl-xL, which revealed the conserved topology amongst all family members. Subsequent structures of Bcl-xL complexes with pro-apoptotic ligands demonstrated the general features of all pro-survival:pro-apoptotic complexes. Structural studies involving Bcl-xL were also the basis for the discovery of the first small-molecule pro-survival protein inhibitors, leading ultimately to the development of a new class of drugs now successfully used for cancer treatment in the clinic. This article will review our current knowledge of the structural biology of Bcl-xL and how this has impacted our understanding of the molecular details of the intrinsic apoptotic pathway. Full article
(This article belongs to the Special Issue Advances in Bcl-xL Research)
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