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Rethinking biology: What role does physical structure play in the development of cells?

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That’s structuralism, in part. Further to Evelyn Fox Keller’s comment that the landscape of biological thought is being “radically reconfigured,” a cancer geneticist writes to say that a tumor’s physical environment fuels its growth and causes treatment resistance:

The forces of cancer

In vitro experiments showing that cancer cells actively migrate in response to fluid flow have supported the hypothesis that fluid escaping from the boundary of a tumor may guide the invasive migration of cancer cells toward lymphatic or blood vessels, potentially encouraging metastasis. There remains controversy over how the fluid forces induce the migration; the cells may respond to chemical gradients created by the cells and distorted by the flowing fluid,8 or the fluid may activate cell mechanosensors. Because of the potential for new therapeutic interventions, the transduction of mechanical fluid forces into biochemical signals by cell mechanosensors is an active area of investigation. In a more direct manner, the fluid flow can physically carry cancer cells to lymph nodes.

And fluid pressure is just one of the many forces in a tumor that can influence its development and progression. Tumors also develop increased solid pressure, as compared with normal tissue, stemming from the uncontrolled division of cancer cells and from the infiltration and proliferation of stromal and immune cells from the surrounding tissue and circulation. High-molecular-weight polysaccharides known as hydrogels found in the extracellular matrix (ECM) also add pressure on a tumor. The most well-studied of these hydrogels is hyaluronan; when the polysaccharide absorbs water, it swells, pressing on surrounding cells and structural elements of the tissue. More. (The Scientist, April 1, 2016)

and

May the Force be with you

The dissection of how cells sense and propagate physical forces is leading to exciting new tools and discoveries in mechanobiology and mechanomedicine.

Of course, mechanical properties and forces aren’t just important in disease, but in health as well. Almost all living cells and tissues exert and experience physical forces that influence biological function. The magnitudes of those forces vary among different cell and tissue types, as do cells’ sensitivities to changes in magnitudes, frequencies, and durations of the forces. Touch, hearing, proprioception, and certain other senses are well-known examples of specialized force sensors. But force detection and sensing are not limited to these special cases; rather, they are shared by all living cells in all tissues and organs. The underlying mechanisms of force generation and detection are not well understood, however, leaving many open questions about force dynamics; the distance over which a force exerts its impact; and how cells convert mechanical signals into biochemical signals and changes in gene expression (The Scientist, February 1, 2017)More.

We may come to understand evolution better if we see what can and can’t happen in physics terms.

See also: Keller: Landscape of biological thought is being “radically reconfigured”

Comments
Consider a magic trick, [...] performed by a world-class magician known as the spliceosome. From a single gene, multiple RNA products emerge. The results are intriguing: some of these transcripts are almost identical, and others are so unique as to exert antagonising functions. However, the trick is straightforward: it is a simple unit rearrangement of the gene sequence. However, how is such a simple trick performed? Let us unravel the magic of alternative splicing.
Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems. Gallego-Paez LM1, Bordone MC1, Leote AC1, Saraiva-Agostinho N1, Ascensão-Ferreira M1, Barbosa-Morais NL2. Hum Genet. 136(9):1015-1042. doi: 10.1007/s00439-017-1790-y.
"Magic trick" is a gross understatement. "Amazing" seems more appropriate. Complex functionally specified informational complexity.Dionisio
November 19, 2017
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Alternative pre-mRNA splicing is a tightly controlled process conducted by the spliceosome, with the assistance of several regulators, resulting in the expression of different transcript isoforms from the same gene and increasing both transcriptome and proteome complexity. The differences between alternative isoforms may be subtle but enough to change the function or localization of the translated proteins. A fine control of the isoform balance is, therefore, needed throughout developmental stages and adult tissues or physiological conditions and it does not come as a surprise that several diseases are caused by its deregulation. The final act of the spliceosome, however, is yet to be fully revealed, as more knowledge is needed regarding the complex regulatory network that coordinates alternative splicing and how its dysfunction leads to disease.
Alternative splicing: the pledge, the turn, and the prestige : The key role of alternative splicing in human biological systems. Gallego-Paez LM1, Bordone MC1, Leote AC1, Saraiva-Agostinho N1, Ascensão-Ferreira M1, Barbosa-Morais NL2. Hum Genet. 136(9):1015-1042. doi: 10.1007/s00439-017-1790-y.
Complex functionally specified informational complexity.
Dionisio
November 19, 2017
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The spliceosome is undoubtedly one of the most complicated machines inside the cell. Unraveling spliceosome biochemistry given the machine’s complexity, malleability, and sheer number of splicing factors is a formidable challenge. [...] many outstanding questions yet remain. Understanding the dynamic transitions of U6 as it progresses between these various complexes will likely require single molecule approaches among many other methods. Single molecule tools will also prove valuable in testing hypotheses related to individual complexes as well. In the new era of spliceosome structures and NGS analysis of spliceosome activity, the future for single molecule studies of the spliceosome looks very bright. It is time for the spliceosome to shine!
Lights, camera, action! Capturing the spliceosome and pre-mRNA splicing with single-molecule fluorescence microscopy. DeHaven AC1,2, Norden IS1,2, Hoskins AA2. Wiley Interdiscip Rev RNA. 7(5):683-701. doi: 10.1002/wrna.1358.
Complex functionally specified informational complexity.Dionisio
November 19, 2017
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The process of removing intronic sequences from a precursor to messenger RNA (pre-mRNA) to yield a mature mRNA transcript via splicing is an integral step in eukaryotic gene expression. Splicing is carried out by a cellular nanomachine called the spliceosome that is composed of RNA components and dozens of proteins. Despite decades of study, many fundamentals of spliceosome function have remained elusive. Recent developments in single-molecule fluorescence microscopy have afforded new tools to better probe the spliceosome and the complex, dynamic process of splicing by direct observation of single molecules. These cutting-edge technologies enable investigators to monitor the dynamics of specific splicing components, whole spliceosomes, and even cotranscriptional splicing within living cells.
Lights, camera, action! Capturing the spliceosome and pre-mRNA splicing with single-molecule fluorescence microscopy. DeHaven AC1,2, Norden IS1,2, Hoskins AA2. Wiley Interdiscip Rev RNA. 7(5):683-701. doi: 10.1002/wrna.1358.
Complex functionally specified informational complexity.Dionisio
November 19, 2017
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Small molecule inhibitors that target components of the spliceosome have great potential as tools to probe splicing mechanism and dissect splicing regulatory networks in cells. Because the spliceosome is a complicated and dynamic macromolecular machine comprised of many RNA and protein components, a variety of compounds that interfere with different aspects of spliceosome assembly is needed to probe its function.
Modulating splicing with small molecular inhibitors of the spliceosome. Effenberger KA1,2, Urabe VK1,2, Jurica MS1,2. Wiley Interdiscip Rev RNA. 8(2). doi: 10.1002/wrna.1381.
Complex functionally specified informational complexity.Dionisio
November 19, 2017
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The supraspliceosome also harbor components for all pre-mRNA processing activities. Thus the supraspliceosome - the endogenous spliceosome - is a stand-alone complete macromolecular machine capable of performing splicing, alternative splicing, and encompass all nuclear pre-mRNA processing activities that the pre-mRNA has to undergo before it can exit from the nucleus to the cytoplasm to encode for protein. Further high-resolution cryo-electron microscopy studies of the endogenous spliceosome are required to decipher the regulation of alternative splicing, and elucidate the network of processing activities within it.
Structural studies of the endogenous spliceosome - The supraspliceosome. Sperling J1, Sperling R2. Methods. 125:70-83. doi: 10.1016/j.ymeth.2017.04.005.
Complex functionally specified informational complexity.Dionisio
November 19, 2017
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Pre-mRNA splicing is executed in mammalian cell nuclei within a huge (21MDa) and highly dynamic molecular machine - the supraspliceosome - that individually package pre-mRNA transcripts of different sizes and number of introns into complexes of a unique structure, indicating their universal nature. Detailed structural analysis of this huge and complex structure requires a stepwise approach using hybrid methods.
Structural studies of the endogenous spliceosome - The supraspliceosome. Sperling J1, Sperling R2. Methods. 125:70-83. doi: 10.1016/j.ymeth.2017.04.005.
Complex functionally specified informational complexity.Dionisio
November 19, 2017
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The complex life of pre-mRNA from transcription to the production of mRNA that can be exported from the nucleus to the cytoplasm to encode for proteins entails intricate coordination and regulation of a network of processing events. Coordination is required between transcription and splicing and between several processing events including 5' and 3' end processing, splicing, alternative splicing and editing that are major contributors to the diversity of the human proteome, and occur within a huge and dynamic macromolecular machine-the endogenous spliceosome. The challenge ahead is to elucidate the structure and function of the endogenous spliceosome and decipher the regulation and coordination of its network of processing activities.
The nuts and bolts of the endogenous spliceosome. Sperling R Wiley Interdiscip Rev RNA. 8(1). doi: 10.1002/wrna.1377.
Complex functionally specified informational complexity.Dionisio
November 18, 2017
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[...] a subset of chromatin proteins is physically in interaction with the enzyme responsible for RNA splicing. In addition, several chromatin proteins not found directly associated with the splicing machinery were also able to influence RNA splicing, suggesting that chromatin compaction very globally plays a role in splicing. [...] assembling DNA with chromatin proteins influences the efficiency of splicing.
A Broad Set of Chromatin Factors Influences Splicing Eric Allemand, Michael P. Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R. Krainer, and Christian Muchardt PLoS Genet. 12(9): e1006318. doi: 10.1371/journal.pgen.1006318
Complex functionally specified informational complexity.Dionisio
November 18, 2017
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Splicing is an RNA editing step allowing to produce multiple transcripts from a single gene. The gene itself is organized in chromatin, associating DNA and multiple proteins. Some proteins regulating the compaction of the chromatin also affect RNA splicing. Yet, it was unclear whether these chromatin proteins were exceptions or whether chromatin very generally affected the outcome of splicing.
A Broad Set of Chromatin Factors Influences Splicing Eric Allemand, Michael P. Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R. Krainer, and Christian Muchardt PLoS Genet. 12(9): e1006318. doi: 10.1371/journal.pgen.1006318
Complex functionally specified informational complexity.Dionisio
November 18, 2017
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Several studies propose an influence of chromatin on pre-mRNA splicing, but it is still unclear how widespread and how direct this phenomenon is. [...] chromatin impacts nascent pre-mRNP in their competence for splicing. [...] numerous chromatin factors associated or not with the spliceosome can affect the outcome of splicing, possibly as a function of the local chromatin environment that by default interferes with the efficiency of splicing.
A Broad Set of Chromatin Factors Influences Splicing Eric Allemand, Michael P. Myers, Jose Garcia-Bernardo, Annick Harel-Bellan, Adrian R. Krainer, and Christian Muchardt PLoS Genet. 12(9): e1006318. doi: 10.1371/journal.pgen.1006318
Complex functionally specified informational complexity.Dionisio
November 18, 2017
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[...] there are numerous target genes that control diverse cellular events. [...] selective activation [...] No specific signal activates all the target genes and no gene is activated by all the signals.
Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71
Did somebody say "selective activation"? Complex functionally specified informational complexity.Dionisio
November 18, 2017
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The balance of protein synthesis and degradation is necessary to maintain the efficiency and accuracy of signal transduction in the cell.
Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71
Did somebody say "efficiency and accuracy"? Complex functionally specified informational complexity.Dionisio
November 18, 2017
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Proteins [...] [...] get regulated at many stages such as protein synthesis, protein folding, post translational modifications (PTMs), and degradation. Protein-protein interactions are another key means of regulating the multicomponent networks. These, altogether, make signal transduction pathway a tightly regulated event.
Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71
Did somebody say "tightly regulated"? Complex functionally specified informational complexity.Dionisio
November 18, 2017
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The major players in the signal transduction pathways are proteins. There are many levels of regulation in such a pathway- from receptors to effectors. Different external cues bring about a diverse array of changes in a cell, with multiple pathways operating with efficiency and specificity.
Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71
Did somebody say "operating with efficiency and specificity"? Complex functionally specified informational complexity.Dionisio
November 18, 2017
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For a cellular function to be carried out, it is imperative that a protein is synthesized, properly folded to its functional form, appropriately modified and localized. It should also be present in appropriate quantity and degraded after its span. All the processes in the cells are subject to this protein quality control system which is mediated by several molecules and pathways. Signal transduction is no exception.
Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 In book: Concepts in Cell Signaling, Chapter: 2, Publisher: Prashant Publishing House New Delhi, Editors: S. Kumar & A. K. Sharma, pp.58-71
Did somebody say 'quality control system'? Complex functionally specified informational complexity.Dionisio
November 18, 2017
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Do the book chapter referenced @67 and the paper referenced @62 share the same title? @67: Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8 @62: Protein Regulation in Signal Transduction Michael J. Lee and Michael B. Yaffe doi: 10.1101/cshperspect.a005918 Cold Spring Harbor Perspectives in Biology Cold Spring Harbor Laboratory PressDionisio
November 18, 2017
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Signal transduction pathways are involved in responses of the cells to different environmental cues and hence, the regulation of these pathways is highly significant. Proteins are the major players in the signaling pathways that are regulated at different stages during their span- from synthesis to degradation. Transcriptional and translational control of the protein synthesis, regulation by protein folding machinery, post-translational modifications, protein localization, protein-protein interactions, and regulated proteolysis- all these regulations work in concert to maintain the specificity and efficiency of the signaling networks. [...] irregularities in signaling networks result in deleterious effects.
Protein Regulation in Signal Transduction Narayanan A, Laxmi S. R and Shashikant R ISBN 978-93-84502-47-8
Did somebody say 'work in concert'? Complex functionally specified informational complexity.Dionisio
November 18, 2017
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Originally based on a graduate course taught by the author, this true classic has once again been extensively updated to incorporate key new findings in biological signaling. With over half of the content re-written, plus 70 brand new and 50 revised figures, this is the most up-to-date textbook on signaling available anywhere. Thanks to its clear structure, hundreds of illustrative drawings, as well as chapter introductions and newly added study questions, this text excels as a companion for a course on biological signaling, and equally as an introductory reference to the field for students and researchers. Generations of students and junior researchers have relied on "the Krauss" to find their way through the bewildering complexity of biological signaling pathways. Table of Contents Preface XXVII 1 Basics of Cell Signaling 1 1.1 Cell Signaling: Why, When, and Where? 1 1.2 Intercellular Signaling 3 1.3 Hormones in Intercellular Signaling 8 1.4 Intracellular Signaling: Basics 15 1.5 Molecular Tools for Intracellular Signaling 18 2 Structural Properties, Regulation and Posttranslational Modification of Signaling Proteins 27 2.1 Modular Structure of Signaling Proteins 27 2.2 Modular Signaling Complexes 31 2.3 Regulation of Signaling Enzymes by Effector Binding 34 2.4 Posttranslational Modifications (PTMs) in Cellular Signaling 36 2.5 Regulation by Protein Phosphorylation 51 2.6 Regulation by Protein Lysine Acetylation 55 2.7 Regulation by Protein Methylation 58 2.8 Ubiquitin Modification of Proteins 62 2.9 Lipidation of Signaling Proteins 90 3 Organization of Signaling 103 3.1 Scaffold Proteins 103 3.2 Signal Processing in Signaling Paths and Signaling Networks 108 3.3 Architecture of Signaling Pathways 113 4 The Regulation of Gene Expression 129 4.1 The Basic Steps of Gene Expression 129 4.2 The Components of the Eukaryotic Transcription Machinery 131 4.3 The Principles of Transcription Regulation 149 4.4 The Control of Transcription Factors 165 4.5 Chromatin Structure and Transcription Regulation 175 5 RNA Processing, Translational Regulation, and RNA Interference 209 5.1 Pre-mRNA Processing 209 5.2 Regulation at the Level of Translation 217 5.3 Regulation by RNA Silencing 229 6 Signaling by Nuclear Receptors 251 6.1 Ligands of Nuclear Receptors (NRs) 252 6.2 Principles of Signaling by Nuclear Receptors (NRs) 254 6.3 Structure of Nuclear Receptors (NRs) 257 6.4 Transcriptional Regulation by NRs 268 6.5 Regulation of Signaling by Nuclear Receptors 274 6.6 Subcellular Localization of NRs 280 6.7 Nongenomic Functions of NRs and their Ligands 284 7 G Protein-Coupled Signal Transmission Pathways 291 7.1 Transmembrane Receptors: General Structure and Classification 291 7.2 Structural Principles of Transmembrane Receptors 294 7.3 G Protein-Coupled Receptors 301 7.4 Regulatory GTPases 320 7.5 The Heterotrimeric G Proteins 327 7.6 Receptor-independent Functions of Heterotrimeric G Proteins 350 7.7 Effector Molecules of G Proteins 352 7.8 GPCR Signaling via Arrestin 363 8 Intracellular Messenger Substances: “Second Messengers” 369 8.1 General Properties of Intracellular Messenger Substances 369 8.2 Cyclic AMP 371 8.3 cGMP and Guanylyl Cyclases 375 8.4 Metabolism of Inositol Phospholipids and Inositol Phosphates 378 8.5 Storage and Release of Ca2þ 383 8.6 Functions of Phosphoinositides 392 8.7 Ca2þ as a Signal Molecule 394 8.8 Diacylglycerol as a Signal Molecule 401 8.9 Other Lipid Messengers: Ceramide, Sphingosine, and Lysophosphatidic Acid 401 8.10 The NO Signaling Molecule 404 9 Ser/Thr-Specific Protein Kinases and Protein Phosphatases 417 9.1 Classification, Structure, and Characteristics of Protein Kinases 417 9.2 Structure and Regulation of Protein Kinases 420 9.3 Protein Kinase A 431 9.4 The PI3 Kinase/Akt Pathway 439 9.5 Protein Kinase C 447 9.6 Ca2þ/Calmodulin-Dependent Protein Kinases, CaM Kinases 455 9.7 Ser/Thr-Specific Protein Phosphatases 461 10 Signal Transmission via Transmembrane Receptors with Tyrosine-Specific Protein Kinase Activity 473 10.1 Structure and Function of RTKs 474 10.2 Downstream Effector Proteins of RTKs 494 10.3 Nonreceptor Tyrosine-Specific Protein Kinases, Non-RTKs 507 10.4 Protein Tyrosine Phosphatases 519 11 Signal Transmission via Ras Proteins 535 11.1 The Ras Superfamily of Monomeric GTPases 535 11.2 GTPase-Activating Proteins (GAPs) of the Monomeric GTPases 539 11.3 Guanine Nucleotide Exchange Factors (GEFs) of the Monomeric GTPases 541 11.4 Guanine Nucleotide Dissociation Inhibitors (GDIs) 544 11.5 The Ras Family of Monomeric GTPases 545 11.6 Raf Kinase as an Effector of Signal Transduction by Ras Proteins 555 11.7 Further Ras Family Members: R-Ras, Ral, and Rap 561 11.8 Reception and Transmission of Multiple Signals by Ras Protein 562 11.9 The Further Branches of the Ras Superfamily 568 12 Intracellular Signal Transduction: The MAP Kinase Pathways 573 12.1 Organization and Components of MAPK Pathways 575 12.2 Regulation of MAPK Pathways by Protein Phosphatases and Inhibitor Proteins 579 12.3 Scaffolding in MAPK Signaling 583 12.4 The Major MAPK Pathways of Mammals 586 13 Membrane Receptors with Associated Tyrosine Kinase Activity 593 13.1 Cytokines and Cytokine Receptors 593 13.2 The Jak-STAT Pathway 608 13.3 T- and B-Cell Receptors 618 13.4 Signal Transduction via Integrins 623 14 Other Transmembrane Receptor Classes: Signaling by TGF-b Receptors, TNF Receptors, Toll Receptors, and Notch 631 14.1 Receptors with Intrinsic Ser/Thr Kinase Activity: The TGF-b Receptor and Smad Protein Signaling 631 14.2 Receptor Regulation by Intramembrane Proteolysis: The Notch Receptor 642 14.3 Tumor Necrosis Factor Receptor (TNFR) Superfamily 648 14.4 Toll-Like Receptor Signaling 653 15 Cell-Cycle Control by External Signaling Pathways 661 15.1 Principles of Cell-Cycle Control 661 15.2 Key Elements of the Cell-Cycle Apparatus 666 15.3 Regulation of the Cell Cycle by Proteolysis 681 15.4 G1 Progression and S Phase Entry 684 15.5 Transit Through S Phase and M Phase 699 15.6 DNA Damage and DNA Replication Checkpoints 702 16 Malfunction of Signaling Pathways and Tumorigenesis: Oncogenes and Tumor Suppressor Genes 715 16.1 Basic Characteristics of Tumor Cells 715 16.2 Mutations in Cancer Cells 715 16.3 Common Physiologic Changes in Tumor Cells: The Hallmarks of Cancer 725 16.4 Signaling Proteins Mutated in Cancer: Oncogenes 729 16.5 Tumor Suppressor Genes: General Functions 741 16.6 Tumor Suppressors: Rb and ARF Proteins 743 16.7 Tumor Suppressor Protein p53 747 16.8 Wnt/b-Catenin Signaling and the Tumor Suppressor APC 770 17 Apoptosis 777 17.1 Overview of Apoptotic Pathways 778 17.2 Caspases: Death by Proteolysis 779 17.3 The Family of Bcl-2 Proteins: Gatekeepers of Apoptosis 786 17.4 The Mitochondrial Pathway of Apoptosis 789 17.5 Death Receptor-Triggered Apoptosis 792 17.6 Links of Apoptosis to Cellular Signaling Pathways 795 Questions 799 References 799 Index 801
Biochemistry of Signal Transduction and Regulation, 5th Edition Gerhard Krauss ISBN: 978-3-527-33366-0
Given the fast pace biology research is going at these days, an over 3 year old textbook might be slightly outdated on some details? Maybe another rewrite is due? Did somebody say 'the bewildering complexity of biological signaling pathways'? Complex functionally specified informational complexity.Dionisio
November 17, 2017
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Trpm2 channels are pro-survival by modulating HIF-1? expression, preserving mitochondrial bioenergetics, decreasing mitochondrial ROS production, and increasing ROS scavenging in cells subjected to oxidative stress. Trpm2 channels protected hearts against I/R injury and tumor cells from doxorubicin toxicity. Targeting Trpm2 channels in the treatment of diseases may result in benefit, e.g., ameliorating cardiac ischemia-reperfusion injury (friend), or harm, e.g., aggravating doxorubicin cardiotoxicity (foe). Therapy with Trpm2 inhibitors may require specific targeting to cancer cells. More detailed investigation needs to be performed before thoughtful and safe therapy centering on Trpm2 channels can be devised.
Transient Receptor Potential-Melastatin Channel Family Member 2: Friend or Foe. Cheung JY, Miller BA1. Trans Am Clin Climatol Assoc. 2017;128:308-329. PMID: 28790515 PMCID: PMC5525431
Complex functionally specified informational complexity.Dionisio
November 17, 2017
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We have shown that Trpm2 channels protect the heart from oxidative stress, specifically I/R injury (36,60) and doxorubicin cardiotoxicity (37). Thus therapy designed to promote Trpm2 activation may be beneficial in acute coronary syndromes, ischemic cardiomyopathy, and doxorubicin cardiotoxicity. On the other hand, Trpm2 channels are involved in cell proliferation and differentiation and sustained indiscriminate Trpm2 activation may not only protect cells from injury including chemotherapy but also promote survival of occult malignant cells. Therefore, therapy must be thoughtful and designed to be organ- and tissue-specific. An in-depth study of Trpm2 is thus warranted in the emerging field of onco-cardiology.
Transient Receptor Potential-Melastatin Channel Family Member 2: Friend or Foe. Cheung JY, Miller BA1. Trans Am Clin Climatol Assoc. 2017;128:308-329. PMID: 28790515 PMCID: PMC5525431
Complex functionally specified informational complexity.Dionisio
November 17, 2017
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Transient receptor potential melastatin 2 (Trpm2) channels are nonvoltage-activated channels permeable to monovalent and divalent cations, and are expressed in heart, brain, kidney, vasculature, and hematopoietic cells. Trpm2 is overexpressed in bladder, lung, breast, liver, head, and neck cancers. Classically, Trpm2 activation induces cell injury and death by Ca2+ overload or enhanced inflammatory response. Recent studies show that Trpm2 protects lungs from endotoxin-induced injury by reducing reactive oxygen species production in phagocytes; and improves cardiac function after ischemia-reperfusion injury by preserving mitochondrial respiration and cellular adenosine triphosphate levels while decreasing reactive oxygen species levels. In neuroblastoma xenografts, Trpm2 overexpression promotes tumor growth through modulation of hypoxia-inducible transcription factor expression and cellular bioenergetics; whereas Trpm2 inhibition results in enhanced sensitivity to doxorubicin. The robust expression in cancer cells and its pro-survival and proliferative properties make Trpm2 a rational target for cancer therapy. Indiscriminate Trpm2 inhibition, however, may engender serious untoward side effects in other vital organs.
Transient Receptor Potential-Melastatin Channel Family Member 2: Friend or Foe. Cheung JY, Miller BA1. Trans Am Clin Climatol Assoc. 2017;128:308-329. PMID: 28790515 PMCID: PMC5525431
Complex functionally specified informational complexity.Dionisio
November 17, 2017
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Cells must respond to a diverse, complex, and ever-changing mix of signals, using a fairly limited set of parts. Changes in protein level, protein localization, protein activity, and protein–protein interactions are critical aspects of signal transduction, allowing cells to respond highly specifically to a nearly limitless set of cues and also to vary the sensitivity, duration, and dynamics of the response. Signal-dependent changes in levels of gene expression and protein synthesis play an important role in regulation of protein levels, whereas posttranslational modifications of proteins regulate their degradation, localization, and functional interactions. Protein ubiquitylation, for example, can direct proteins to the proteasome for degradation or provide a signal that regulates their interactions and/or location within the cell. Similarly, protein phosphorylation by specific kinases is a key mechanism for augmenting protein activity and relaying signals to other proteins that possess domains that recognize the phosphorylated residues.
Protein Regulation in Signal Transduction Michael J. Lee and Michael B. Yaffe doi: 10.1101/cshperspect.a005918 Cold Spring Harbor Perspectives in Biology Cold Spring Harbor Laboratory Press
Complex functionally specified informational complexity.Dionisio
November 17, 2017
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A final intriguing case is that of cotranslational interaction between human mitochondrially encoded COX1 and C12ORF62 [...] The mechanistic details of this process are not yet fully understood, but it has a fascinating implication, [...] [...] to further understand the role of cotranslational assembly in normal biological function, as well as its potential implications mitigating the DN effect in inherited and de novo genetic disorders, there is a need for new tools and much more experimental characterization cotranslational processes.
Regulation, evolution and consequences of cotranslational protein complex assembly Eviatar Natan 1, Jonathan N Wells 2, Sarah A Teichmann 3, Joseph A Marsh 2 Science Direct Current Opinion in Structural Biology Volume 42, Pages 90-97 DOI: https://doi.org/10.1016/j.sbi.2016.11.023
Did somebody say 'intriguing'? Did somebody say 'fascinating'? Complex functionally specified informational complexity.Dionisio
November 17, 2017
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Clearly, other factors such as chaperones may participate in ensuring correct assembly both for homomers and heteromers. Chaperones play an essential role in avoiding misfolding or aggregation, thus promoting the formation of native tertiary and quaternary protein structure. The mechanistic details of how they act vary dramatically, and chaperones as a whole encompass a wide variety of unrelated protein families The action of chaperones is particularly important for eukaryotic proteins, which are typically longer than those from prokaryotes, often comprise multiple domains, and have a higher incidence of intrinsically disordered and flexible regions [...]
Regulation, evolution and consequences of cotranslational protein complex assembly Eviatar Natan 1, Jonathan N Wells 2, Sarah A Teichmann 3, Joseph A Marsh 2 Science Direct Current Opinion in Structural Biology Volume 42, Pages 90-97 DOI: https://doi.org/10.1016/j.sbi.2016.11.023
Complex functionally specified informational complexity.Dionisio
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[...] the exact frequency at which cotranslational folding occurs in either prokaryotes or eukaryotes is unknown [...] There are several reasons why proteins might acquire secondary structure during translation, sometimes even while still inside the ribosome exit tunnel [...] The cell broadly regulates both cis and trans mechanisms.
Regulation, evolution and consequences of cotranslational protein complex assembly Eviatar Natan 1, Jonathan N Wells 2, Sarah A Teichmann 3, Joseph A Marsh 2 Science Direct Current Opinion in Structural Biology Volume 42, Pages 90-97 DOI: https://doi.org/10.1016/j.sbi.2016.11.023
Complex functionally specified informational complexity.Dionisio
November 17, 2017
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[...] there are still unanswered questions about how the cell regulates protein complex assembly, and where assembly actually occurs within the cell. A logical place to begin addressing this is in the initial stages of protein synthesis and folding.
Regulation, evolution and consequences of cotranslational protein complex assembly Eviatar Natan 1, Jonathan N Wells 2, Sarah A Teichmann 3, Joseph A Marsh 2 Science Direct Current Opinion in Structural Biology Volume 42, Pages 90-97 DOI: https://doi.org/10.1016/j.sbi.2016.11.023
Complex functionally specified informational complexity.Dionisio
November 17, 2017
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Proteins are synthesized as linear polymers and have to fold into their native structure to fulfil various functions in the cell. Folding can start co-translationally when the emerging peptide is still attached to the ribosome and is guided by the environment of the polypeptide exit tunnel and the kinetics of translation. Major questions are: When does co-translational folding begin? What is the role of the ribosome in guiding the nascent peptide towards its native structure? How does translation elongation kinetics modulate protein folding? Here we suggest how novel structural and biophysical approaches can help to probe the interplay between the ribosome and the emerging peptide and present future challenges in understanding co-translational folding.
Co-translational protein folding: progress and methods Michael Thommen, Wolf Holtkamp, Marina V Rodnina Current Opinion in Structural Biology Volume 42, Pages 83-89 DOI: https://doi.org/10.1016/j.sbi.2016.11.020
Did somebody say 'future challenges'? Complex functionally specified informational complexity.Dionisio
November 17, 2017
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Contemporary protein structure is a result of the trade off between the laws of physics and the evolutionary selection. The polymer nature of proteins played a decisive role in establishing the basic structural and functional units of soluble proteins. We discuss how these elementary building blocks work in the hierarchy of protein domain structure, co-translational folding, as well as in enzymatic activity and molecular interactions. Next, we consider modulators of the protein function, such as intermolecular interactions, disorder-to-order transitions, and allosteric signaling, acting via interference with the protein's structural dynamics. We also discuss the post-translational modifications, which is a complementary intricate mechanism evolved for regulation of protein functions and interactions. In conclusion, we assess an anticipated contribution of discussed topics to the future advancements in the field.
Protein function machinery: from basic structural units to modulation of activity Igor N Berezovsky 1, 2, Enrico Guarnera 1, Zejun Zheng 1, Birgit Eisenhaber 1, Frank Eisenhaber 1, 3 Current Opinion in Structural Biology Volume 42, Pages 67-74 DOI: https://doi.org/10.1016/j.sbi.2016.10.021
Parole, parole, parole... Where's the beef? Complex functionally specified informational complexity.Dionisio
November 17, 2017
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@46-47: https://www.researchgate.net/profile/Igor_Berezovsky/publication/308912133_Basic_units_of_protein_structure_folding_and_function/links/597efbdfaca272d56817fa17/Basic-units-of-protein-structure-folding-and-function.pdf Complex functionally specified informational complexity.Dionisio
November 17, 2017
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