A 'multiscale' assessment of the molecular mechanisms underlying the pro-survival Bcl-2 protein members in cancer
(2018) BINP51 20172Degree Projects in Bioinformatics
- Abstract
- Apoptosis is a vital physiological defence mechanism against tumorigenesis and critical for embryogenesis, tissue homeostasis, and discharging damaged or infected cells. Protein members of the B-cell lymphoma-2 (Bcl-2) family regulates the cellular commitment to cell survival or programmed cell death by intrinsic (mitochondrial) apoptosis. In response to intracellular stresses, this apoptotic balance is governed by interactions on the outer mitochondrial membrane, by three distinct subgroups; the activator/sensitizer BH3 (Bcl-2 homology 3)-only proteins, the pro-survival inhibitor proteins, and the pro-apoptotic executioner proteins. Inhibition of apoptosis, e.g., deregulation or functional impairment, by pro-survival proteins can lead to... (More)
- Apoptosis is a vital physiological defence mechanism against tumorigenesis and critical for embryogenesis, tissue homeostasis, and discharging damaged or infected cells. Protein members of the B-cell lymphoma-2 (Bcl-2) family regulates the cellular commitment to cell survival or programmed cell death by intrinsic (mitochondrial) apoptosis. In response to intracellular stresses, this apoptotic balance is governed by interactions on the outer mitochondrial membrane, by three distinct subgroups; the activator/sensitizer BH3 (Bcl-2 homology 3)-only proteins, the pro-survival inhibitor proteins, and the pro-apoptotic executioner proteins. Inhibition of apoptosis, e.g., deregulation or functional impairment, by pro-survival proteins can lead to imbalance in tissue homeostasis and overexpression of pro-survival proteins can be oncogenic. The critical role in homeostasis and tumorigenesis, coupled with progress in structural elucidation of the protein-protein interaction in the Bcl-2 family has lead to pro-survival Bcl-2 proteins being considered promising therapeutic targets in anticancer treatments. A better comprehension of the transcriptomic signature and molecular mechanism underlying pro-survival Bcl-2 proteins in different cancer types, could help to clarify their role in cancer development and will likely guide advancement in drug discovery, targeting these proteins. Here, we shed light on the molecular mechanisms underlying the pro-survival Bcl-2 proteins by proposing a `multiscale' approach to cancer bioinformatics. We will start from transcriptomic signatures of the pro-survival proteins and their interaction partners, in breast cancer patients. We will then zoom in, at the molecular and structural level, on the most interesting interactions, using what we call `the computational microscope' for cancer biology. Through this approach we aim at uncovering the gene expression landscape and assess the structural and functional effects of mutations on the binding affinity and structural stability. Moreover, we apply a high-throughput in silico mutagenesis approach to identify functionally important residues in the pro-survival members and their interactors. (Less)
- Popular Abstract
- Understanding the role of pro-survival Bcl-2 proteins in cancer
Programmed cell death or apoptosis is the process in which a cell commits "suicide". It is a vital physiological process and essential to human development. When a cell is damaged, apoptosis allows that cell to be disposed of, in an orderly way that protects surrounding cells from harmful cell content. When the process of apoptosis is disrupted, cells that should be eliminated may survive and these may exhibit excessive cellular proliferation, resulting in the development of cancer. The cellular decision making-process, between cell survival and cell death is controlled by protein members of the B-cell lymphoma-2 (Bcl-2) family.
Regulation of apoptosis is orchestrated by... (More) - Understanding the role of pro-survival Bcl-2 proteins in cancer
Programmed cell death or apoptosis is the process in which a cell commits "suicide". It is a vital physiological process and essential to human development. When a cell is damaged, apoptosis allows that cell to be disposed of, in an orderly way that protects surrounding cells from harmful cell content. When the process of apoptosis is disrupted, cells that should be eliminated may survive and these may exhibit excessive cellular proliferation, resulting in the development of cancer. The cellular decision making-process, between cell survival and cell death is controlled by protein members of the B-cell lymphoma-2 (Bcl-2) family.
Regulation of apoptosis is orchestrated by interactions between three distinct subgroups of the Bcl-2 family: (i) the activator/sensitizer BH3 (Bcl-2 homology 3)-only proteins, (ii) the pro-survival, cell death inhibitor proteins, and (iii) the pro-apoptotic cell death executioner proteins. The BH3-only proteins are responsible for sensing cellular damage, whereupon they either activate the pro-apoptotic executioner members or sensitizes the pro-survival inhibitor proteins. Both of which leads to the elimination of the damaged cell. Pro-survival Bcl-2 proteins exploit their function by binding to pro-apoptotic proteins, preventing elimination of damaged cells.
The interaction between the three subgroups of proteins is mediated through a small amino acid sequence termed the BH3-motif (a motif is a widespread sequence pattern that has a biological function). The inhibition of apoptosis by pro-survival members can enable cancer cells to escape cell death and pro-survival members of the Bcl-2 family have been found to be overexpressed in a range of cancers. That is, the relative abundance of pro-survival proteins has been found to be higher, in some cancers, in respect to normal tissue.
Because of their pivotal role as inhibitors of apoptosis, pro-survival Bcl-2 members are considered to be promising therapeutic targets in anti-cancer treatments. That is, the intriguing prospective in designing drugs that can induce cancer cell death by preventing these members from inhibiting apoptosis. Though progress has been made in the development of drugs (BH3-mimetics) mimicking the BH3-only sensitizers, common for these drugs are that they have not been successful in discriminating between different pro-survival members.
Additional knowledge of the abundance of different pro-survival members in different cancer types, coupled with a better understanding of their interaction and functionality on a molecular level, will provide a solid foundation for the development of BH3-mimetics with increased sensitivity and specificity.
We have proposed a computational workflow to shed light on the role of the pro-survival Bcl-2 members, by bridging two of the major branches of cancer bioinformatics: (i) analysis of high-throughput sequencing data, and (ii) molecular modeling.
We started from transcriptomic profiles of the pro-survival proteins in cancer patients, with the aim of clarifying their abundance in cancer tissue, compared to normal tissue.
Next, we zoomed in at the molecular and structural level of the pro-survival members and their interactors, with what we call ‘the computational microscope’ for cancer biology, allowing us to predict amino acids important for protein-protein interactions.
To demonstrate this approach, we conducted a study using breast cancer and found a pro-survival protein member to be overexpressed in breast cancer compared to normal tissue. Moreover, we identified several interactors containing small linear sequences resemblaning the BH3-motif found in BH3-only proteins.
Our study highlights the prospects of an integrative bioinformatic approach for an increased understanding of the pro-survival Bcl-2 proteins and their interactions.
Master’s Degree Project in Bioinformatics 45 credits 2018
Department of Biology, Lund University
Advisors: Thilde Bagger Terkelsen, Matteo Lambrughi and Elena Papaleo
Danish Cancer Society Research Center, Computational Biology Laboratory, Copenhagen, Denmark (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/8953112
- author
- Kønig, Simon Mathis
- supervisor
- organization
- course
- BINP51 20172
- year
- 2018
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 8953112
- date added to LUP
- 2018-06-26 15:23:45
- date last changed
- 2018-06-26 15:23:45
@misc{8953112,
abstract = {{Apoptosis is a vital physiological defence mechanism against tumorigenesis and critical for embryogenesis, tissue homeostasis, and discharging damaged or infected cells. Protein members of the B-cell lymphoma-2 (Bcl-2) family regulates the cellular commitment to cell survival or programmed cell death by intrinsic (mitochondrial) apoptosis. In response to intracellular stresses, this apoptotic balance is governed by interactions on the outer mitochondrial membrane, by three distinct subgroups; the activator/sensitizer BH3 (Bcl-2 homology 3)-only proteins, the pro-survival inhibitor proteins, and the pro-apoptotic executioner proteins. Inhibition of apoptosis, e.g., deregulation or functional impairment, by pro-survival proteins can lead to imbalance in tissue homeostasis and overexpression of pro-survival proteins can be oncogenic. The critical role in homeostasis and tumorigenesis, coupled with progress in structural elucidation of the protein-protein interaction in the Bcl-2 family has lead to pro-survival Bcl-2 proteins being considered promising therapeutic targets in anticancer treatments. A better comprehension of the transcriptomic signature and molecular mechanism underlying pro-survival Bcl-2 proteins in different cancer types, could help to clarify their role in cancer development and will likely guide advancement in drug discovery, targeting these proteins. Here, we shed light on the molecular mechanisms underlying the pro-survival Bcl-2 proteins by proposing a `multiscale' approach to cancer bioinformatics. We will start from transcriptomic signatures of the pro-survival proteins and their interaction partners, in breast cancer patients. We will then zoom in, at the molecular and structural level, on the most interesting interactions, using what we call `the computational microscope' for cancer biology. Through this approach we aim at uncovering the gene expression landscape and assess the structural and functional effects of mutations on the binding affinity and structural stability. Moreover, we apply a high-throughput in silico mutagenesis approach to identify functionally important residues in the pro-survival members and their interactors.}},
author = {{Kønig, Simon Mathis}},
language = {{eng}},
note = {{Student Paper}},
title = {{A 'multiscale' assessment of the molecular mechanisms underlying the pro-survival Bcl-2 protein members in cancer}},
year = {{2018}},
}