scholarly journals The BRCA1 Breast Cancer Suppressor: Regulation of Transport, Dynamics, and Function at Multiple Subcellular Locations

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Beric R. Henderson
Keyword(s):  
Dna Repair ◽  
Nuclear Export ◽  
Cell Cycle Progression ◽  
Cellular Functions ◽  
Nuclear Localization Signals ◽  
Transport Dynamics ◽  
Ubiquitin E3 Ligase ◽  
Cancer Mutations ◽  
Dynamics And Function ◽  
And Function

Inherited mutations in theBRCA1gene predispose to a higher risk of breast/ovarian cancer. The BRCA1 tumor suppressor is a 1863 amino acid protein with multiple protein interaction domains that facilitate its roles in regulating DNA repair and maintenance, cell cycle progression, transcription, and cell survival/apoptosis. BRCA1 was first identified as a nuclear phosphoprotein, but has since been shown to contain different transport sequences including nuclear export and nuclear localization signals that enable it to shuttle between specific sites within the nucleus and cytoplasm, including DNA repair foci, centrosomes, and mitochondria. BRCA1 nuclear transport and ubiquitin E3 ligase enzymatic activity are tightly regulated by the BRCA1 dimeric binding partner BARD1 and further modulated by cancer mutations and diverse signaling pathways. This paper will focus on the transport, dynamics, and multiple intracellular destinations of BRCA1 with emphasis on how regulation of these events has impact on, and determines, a broad range of important cellular functions.

scholarly journals Bioinformatic Analysis of Structure and Function of Lim Domains of Zyxin Family Proteins

2020 ◽  
Author(s):  
Mohammad Quadir Siddiqui ◽  
Maulik D. Badmalia ◽  
Trushar R. Patel
Keyword(s):  
Protein Interactions ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
Bioinformatic Analysis ◽  
Elastic Network Model ◽  
Cellular Functions ◽  
Consensus Analysis ◽  
Mutational Frequency ◽  
Lim Domains ◽  
And Function

AbstractLim domains are one of the most abundant types of zinc-finger domains and are linked with diverse cellular functions ranging from cytoskeleton maintenance to gene regulation. Zyxin family Lim domains perform the critical cellular functions and are indispensable for cellular integrity. Despite having these important functions the fundamental nature of the sequence, structure, functions, and interactions of the Zyxin family Lim domains are largely unknown. Therefore, we have used a set of in-silico tools and bioinformatics databases to distill the fundamental properties of the Zyxin family proteins/Lim domains from their amino acid sequence, phylogeny, biochemical analysis, post-translational modifications, structure dynamics, molecular interactions, and functions. Consensus analysis of the nuclear export signal suggests a conserved Leucine-rich motif composed of LxxLxL/LxxxLxL. Molecular modeling and structural analysis demonstrate that Lim domains of the members of the Zyxin family proteins share similarities with transcriptional regulators, suggesting they could interact with nucleic acids as well. Normal mode, Covariance, and Elastic Network Model analysis of Zyxin family Lim domains suggest only the Lim1 region has similar internal dynamics properties, compared to Lim2/3. Protein expression/mutational frequency studies of the Zyxin family demonstrated higher expression and mutational frequency rates in various malignancies. Protein-protein interactions indicate that these proteins could facilitate metabolic rewiring and oncogenic addiction paradigm. Our comprehensive analysis of the Zyxin family proteins indicates that the Lim domains function in a variety of ways and could be implicated in rational protein engineering and might lead as a better therapeutic target for various diseases, including cancers.

scholarly journals MYC activity is required for maintenance of the Neuromesodermal Progenitor signalling network and for correct timing of segmentation clock gene oscillations

2017 ◽  
Author(s):  
Ioanna Mastromina ◽  
Laure Verrier ◽  
Kate G. Storey ◽  
J. Kim Dale
Keyword(s):  
Cell Cycle Progression ◽  
The Body ◽  
Body Axis ◽  
Cellular Functions ◽  
Segmentation Clock ◽  
Signalling Network ◽  
Undifferentiated State ◽  
Somite Formation ◽  
Axis Elongation ◽  
And Function

AbstractThe Myc transcriptional regulators are implicated in a range of cellular functions, including proliferation, cell cycle progression, metabolism and pluripotency maintenance. Here, we investigated the expression, regulation and function of Myc during mouse embryonic axis elongation and segmentation. Expression of both cMyc and MycN in the domains where neuromesodermal progenitors (NMPs) and underlying caudal pre-somitic mesoderm (cPSM) cells reside is coincident WNT and FGF signals; factors known to maintain progenitors in an undifferentiated state. Pharmacological inhibition of MYC activity, downregulates expression of WNT/FGF components. In turn, we find that cMyc expression is WNT, FGF and NOTCH regulated, placing it centrally in the signalling circuit that operates in the tail end that both sustains progenitors and drives maturation of the PSM into somites. Interfering with MYC function in the PSM, where it displays oscillatory expression, delays the timing of segmentation clock oscillations and thus of somite formation. In summary, we identify Myc as a component that links NMP maintenance and PSM maturation during the body axis elongation stages of mouse embryogenesis.Summary StatementMYC operates in a positive feedback loop with WNT/FGF signals to maintain the progenitors which facilitate body axis elongation while its activity is crucial for timing of the segmentation clock.

scholarly journals STIM and Orai proteins as novel targets for cancer therapy. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis

2015 ◽  
Vol 309 (7) ◽  
pp. C457-C469 ◽  
Author(s):  
Ayushi Vashisht ◽  
Mohamed Trebak ◽  
Rajender K. Motiani
Keyword(s):  
Cancer Therapy ◽  
Cell Cycle Progression ◽  
Cancer Metastasis ◽  
Cancer Therapeutics ◽  
Vital Role ◽  
Cellular Migration ◽  
Cellular Functions ◽  
Altered Expression ◽  
Influx Pathways ◽  
And Function

Calcium (Ca2+) regulates a plethora of cellular functions including hallmarks of cancer development such as cell cycle progression and cellular migration. Receptor-regulated calcium rise in nonexcitable cells occurs through store-dependent as well as store-independent Ca2+ entry pathways. Stromal interaction molecules (STIM) and Orai proteins have been identified as critical constituents of both these Ca2+ influx pathways. STIMs and Orais have emerged as targets for cancer therapeutics as their altered expression and function have been shown to contribute to tumorigenesis. Recent data demonstrate that they play a vital role in development and metastasis of a variety of tumor types including breast, prostate, cervical, colorectal, brain, and skin tumors. In this review, we will retrospect the data supporting a key role for STIM1, STIM2, Orai1, and Orai3 proteins in tumorigenesis and discuss the potential of targeting these proteins for cancer therapy.

scholarly journals A phospho-regulated ensemble signal motif of α-TAT1 drives dynamic microtubule acetylation

2020 ◽  
Author(s):  
Abhijit Deb Roy ◽  
Evan G. Gross ◽  
Gayatri S. Pillai ◽  
Shailaja Seetharaman ◽  
Sandrine Etienne-Manneville ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Cellular Functions ◽  
Intrinsically Disordered ◽  
Phosphorylated Form ◽  
C Terminus ◽  
Cancer Mutations ◽  
Functional Consequences ◽  
Dynamic Microtubule

AbstractSpatiotemporal patterns of microtubule modifications such as acetylation underlie diverse cellular functions. While the molecular identity of the acetylating agent, α-tubulin N-acetyltransferase 1 (α-TAT1), as well as the functional consequences of microtubule acetylation have been revealed, the molecular mechanisms that regulate multi-tasking α-TAT1 action for dynamic acetylation remain obscure. Here we identified a signal motif in the intrinsically disordered C-terminus of α-TAT1, which comprises three functional elements - nuclear export, nuclear import and cytosolic retention. Their balance is tuned via phosphorylation by serine-threonine kinases to determine subcellular localization of α-TAT1. While the phosphorylated form binds to 14-3-3 adapters and accumulates in the cytosol for maximal substrate access, the non-phosphorylated form is sequestered inside the nucleus, thus keeping microtubule acetylation minimal. As cancer mutations have been reported to this motif, the unique ensemble regulation of α-TAT1 localization may hint at a role of microtubule acetylation in aberrant physiological conditions.

scholarly journals Ena/VASP regulates mDia2-initiated filopodial length, dynamics, and function

2014 ◽  
Vol 25 (17) ◽  
pp. 2604-2619 ◽  
Author(s):  
Melanie Barzik ◽  
Leslie M. McClain ◽  
Stephanie L. Gupton ◽  
Frank B. Gertler
Keyword(s):  
Molecular Mechanisms ◽  
Cell Spreading ◽  
Model System ◽  
Regulatory Proteins ◽  
Signaling Cascades ◽  
Cellular Functions ◽  
Actin Organization ◽  
Actin Regulatory Proteins ◽  
Dynamics And Function ◽  
And Function

Filopodia are long plasma membrane extensions involved in the formation of adhesive, contractile, and protrusive actin-based structures in spreading and migrating cells. Whether filopodia formed by different molecular mechanisms equally support these cellular functions is unresolved. We used Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP)–deficient MVD7 fibroblasts, which are also devoid of endogenous mDia2, as a model system to investigate how these different actin regulatory proteins affect filopodia morphology and dynamics independently of one another. Filopodia initiated by either Ena/VASP or mDia2 contained similar molecular inventory but differed significantly in parameters such as number, length, F-actin organization, lifetime, and protrusive persistence. Moreover, in the absence of Ena/VASP, filopodia generated by mDia2 did not support initiation of integrin-dependent signaling cascades required for adhesion and subsequent lamellipodial extension, thereby causing a defect in early cell spreading. Coexpression of VASP with constitutively active mDia2M/A rescued these early adhesion defects. We conclude that Ena/VASP and mDia2 support the formation of filopodia with significantly distinct properties and that Ena/VASP regulates mDia2-initiated filopodial morphology, dynamics, and function.

Establishing a model to demonstrate physical and mathematical properties of chromatin fibres in fission yeast cells - Research in the Molecular Biophysics Lab at Hiroshima University

Impact ◽  
2018 ◽  
Vol 2018 (3) ◽  
pp. 89-91
Author(s):  
Shin-ichi Tate
Keyword(s):  
Molecular Biology ◽  
Yeast Cells ◽  
Molecular Architecture ◽  
Ministry Of Education ◽  
Cellular Functions ◽  
Sports Science ◽  
Cellular Events ◽  
And Function ◽  
Education Culture ◽  
Open The Doors

The field of molecular biology has provided great insights into the structure and function of key molecules. Thanks to this area of research, we can now grasp the biological details of DNA and have characterised an enormous number of molecules in massive data bases. These 'biological periodic tables' have allowed scientists to connect molecules to particular cellular events, furthering scientific understanding of biological processes. However, molecular biology has yet to answer questions regarding 'higher-order' molecular architecture, such as that of chromatin. Chromatin is the molecular material that serves as the building block for chromosomes, the structures that carry an organism's genetic information inside of the cell's nucleus. Understanding the physical properties of chromatin is crucial in developing a more thorough picture of how chromatin's structure relate to its key cellular functions. Moreover, by establishing a physical model of chromatin, scientists will be able to open the doors into the true inner workings of the cell nucleus. Professor Shin-ichi Tate and his team of researchers at Hiroshima University's Research Center for the Mathematics on Chromatin Live Dynamics (RcMcD), are attempting to do just that. Through a five-year grant funded by the Platform for Dynamic Approaches to Living Systems from the Ministry of Education, Culture, Sports, Science and Technology, Tate is aiming to gain a clearer understanding of the structure and dynamics of chromatin.

scholarly journals Bend, Push, Stretch: Remarkable Structure and Mechanics of Single Intermediate Filaments and Meshworks

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1960
Author(s):  
K. Tanuj Sapra ◽  
Ohad Medalia
Keyword(s):  
Intermediate Filaments ◽  
Eukaryotic Cell ◽  
Coiled Coils ◽  
Cellular Functions ◽  
Mechanical Pressure ◽  
Mechanical Feature ◽  
Cellular Processes ◽  
Nuclear Lamins ◽  
Filament Networks ◽  
And Function

The cytoskeleton of the eukaryotic cell provides a structural and functional scaffold enabling biochemical and cellular functions. While actin and microtubules form the main framework of the cell, intermediate filament networks provide unique mechanical properties that increase the resilience of both the cytoplasm and the nucleus, thereby maintaining cellular function while under mechanical pressure. Intermediate filaments (IFs) are imperative to a plethora of regulatory and signaling functions in mechanotransduction. Mutations in all types of IF proteins are known to affect the architectural integrity and function of cellular processes, leading to debilitating diseases. The basic building block of all IFs are elongated α-helical coiled-coils that assemble hierarchically into complex meshworks. A remarkable mechanical feature of IFs is the capability of coiled-coils to metamorphize into β-sheets under stress, making them one of the strongest and most resilient mechanical entities in nature. Here, we discuss structural and mechanical aspects of IFs with a focus on nuclear lamins and vimentin.

scholarly journals Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 336
Author(s):  
Roberta Melchionna ◽  
Paola Trono ◽  
Annalisa Tocci ◽  
Paola Nisticò
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Actin Dynamics ◽  
Human Tissues ◽  
Cellular Functions ◽  
Tgfβ Signaling ◽  
Physical Mechanisms ◽  
And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

Sign in / Sign up

Export Citation Format

Share Document