Polyglutamine-repeat diseases are neurodegenerative ailments elicited by glutamine-encoding CAG nucleotide expansions within endogenous human genes. Despite efforts to understand the basis of these diseases, the precise mechanism of cell death remains stubbornly unclear. Much of the data seems consistent with a model in which toxicity is an inherent property of the polyglutamine repeat, whereas host protein sequences surrounding the polyQ expansion modulate severity, age of onset, and cell specificity. Recently, a gene, pqn-41encoding a glutamine-rich protein was found to promote normally-occurring non-apoptotic cell death in C. elegans. Here we review evidence for toxic and modulatory roles for polyQ repeats and their host proteins, respectively, and suggest similarities with pqn-41 function. We explore the hypothesis that toxicity mediated by glutamine-rich motifs may be important not only in pathology, but also in normal development.
To function as an intact barrier, epithelia must maintain constant cell numbers despite high rates of turnover. If the rate of death exceeds proliferation, epithelial barrier function could become compromised; if it lags behind proliferation, cells could amass into tumors. Although the balance between cell death and division is critical for preventing pathology, most studies focus on each process in isolation. Loss of contact inhibition is a hallmark of cancer cells and cell contacts appear important for linking rates of cell division and death. However, epithelial cells continuously divide and die while maintaining contacts with each other, so other factors must control this balance. Recent studies find that cell crowding forces from cell proliferation can drive cells to die by extrusion from the epithelium. Factors that alter this response to cell crowding may lead to barrier function diseases or promote hyperplasia and cancer.
The nucleus is a spatially organized compartment. The most obvious way in which this is achieved is at the level of chromosomes. The positioning of chromosomes with respect to nuclear landmarks and with respect to each other is both non-random and cell-type specific. This suggests that cells possess molecular mechanisms to influence the folding and disposition of chromosomes within the nucleus. The localization of many proteins is also heterogeneous within the nucleus. Therefore, chromosome folding and the localization of proteins leads to a model in which individual genes are positioned in distinct protein environments that can impact their transcriptional state. Here, we focus on the spatial organization of the nucleus and how it impacts gene expression.
X-chromosome inactivation has long served as an experimental model system for understanding the epigenetic regulation of gene expression. Central to this phenomenon is the long, non-coding RNA Xist that is specifically expressed from the inactive X chromosome and spreads along the entire length of the chromosome in cis. Recently, two of the proteins originally identified as components of the nuclear scaffold/matrix (S/MAR-associated proteins) have been shown to control the principal features of X-chromosome inactivation; specifically, context-dependent competency and the chromosome-wide association of Xist RNA. These findings implicate the involvement of nuclear S/MAR-associated proteins in the organization of epigenetic machinery. Here, we describe a model for the functional role of S/MAR-associated proteins in the regulation of key epige-netic processes.
Bcl-2 family proteins regulate apoptosis in animals. This protein family includes several homologous proteins and a collection of other proteins lacking sequence similarity except for a BH3 motif. Thus, membership in the Bcl-2 family requires only one of the four BH (Bcl-2 homology) motifs. On this basis, a growing number of diverse BH3-only proteins are being reported. While compelling cell biological and biophysical evidence validates many BH3-only proteins, claims about significant BH3 sequence similarity are often unfounded. Computational and phylogenetic analyses suggest that only some BH3 motifs arose by divergent evolution from a common ancestor (homology), while others arose by convergent evolution or random coincidence (homoplasy), challenging current assumptions about which proteins constitute the extended Bcl-2 family.
Bcl-2 family; BH3; sequence motifs; protein homology; apoptosis; evolution
Cell cycle transitions are driven by the periodic oscillations of cyclins, which bind and activate CDKs (cyclin-dependent kinases) to phosphorylate target substrates. Cyclin F uses a substrate recruitment strategy similar to that of the other cyclins, but its associated catalytic activity is substantially different. Indeed, cyclin F is the founding member of the F-box family of proteins, which are the substrate recognition subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes. Here, we discuss cyclin F function and recently identified substrates of SCFcyclin F involved in dNTP production, centrosome duplication, and spindle formation. We highlight the relevance of cyclin F in controlling genome stability through ubiquitin-mediated proteolysis and the implications for cancer development.
Nuclear pore complex (NPC) proteins are known for their critical roles in regulating nucleocytoplasmic traffic of macromolecules across the nuclear envelope. However, recent findings suggest that some nucleoporins (Nups), including Nup98, have additional functions in developmental gene regulation. Nup98, which exhibits transcription-dependent mobility at the NPC but can also bind chromatin away from the nuclear envelope, is frequently involved in chromosomal translocations in a subset of patients suffering from acute myeloid leukemia (AML). A common paradigm suggests that Nup98 translocations cause aberrant transcription when they are recuited to aberrant genomic loci. Importantly, this model fails to account for the potential loss of wild type (WT) Nup98 function in the presence of Nup98 translocation mutants. Here we examine how the cell might regulate Nup98 nucleoplasmic protein levels to control transcription in healthy cells. In addition, we discuss the possibility that dominant negative Nup98 fusion proteins disrupt the transcriptional activity of WT Nup98 in the nucleoplasm to drive AML.
Nup98; Nup96; nuclear pore complex; chromatin; transcription; chromosomal translocation; acute myeloid leukemia
Many cell phenomena that involve shape changes are affected by the intrinsic deformability of the plasma membrane. Far from being a passive participant, the plasma membrane is now known to physically, as well as biochemically, influence cell processes ranging from vesicle trafficking to actin assembly. Here we review current understanding of how changes in plasma membrane tension regulate cell shape and movement as well as how cells sense plasma membrane tension.
membrane tension; motility; cell shape
Members of the myosin-I family of molecular motors are expressed in many eukaryotes where they are involved in a multitude of critical processes. Humans express 8 distinct members of the myosin-I family, making it the second largest family of myosins expressed in humans. Despite the high degree of sequence conservation in the motor and light chain binding domains of these myosins, recent studies have revealed surprising diversity of function and regulation arising from isoform-specific differences in these domains. Here we review the regulation of myosin-I function and localization by the motor and light chain binding domains.
myosin-I; mechanochemistry; light chain binding domain; motor domain
It has been only 15 years since studies began on the molecular mechanisms underlying mitochondrial fission and fusion using simple model organisms such as Drosophila, yeast, and C. elegans. Beyond the primary functions of mitochondrial fission and fusion in controlling organelle shape, size and number, it became clear that these dynamic processes are also critical for regulating cell death, mitophagy and organelle distribution. Now, studies suggest that prominent changes occur in mitochondrial dynamics in a broad array of neurodegenerative disease, and there is substantial evidence suggesting a key role in disease pathogenesis, as neurons are among the most energy-consuming cell types and have a highly developed cell shape. Here, we review the recent findings on mitochondrial dynamics in neurodegeneration.
mitochondria; fission; fusion; dynamin-related GTPase; neurodegeneration
Substantial progress has been made in recent years toward understanding the molecular mechanisms by which tumor cells, and the supporting stroma, degrade confining matrix during migration. Significant attention has been focused toward understanding the biology of several dynamic and distinct, but remarkably related, cell structures that include lamellipodia, focal adhesions, filopodia, podosomes, and invadopodia. How these invasive organelles assemble and function is a topic of intense study. Most exciting has been the recent progress made combining advanced microscopic technologies with a wide variety of different 3D matrices, tissue explants, or even living model organisms. From these approaches, it has become increasingly evident that the conventional definitions for these invasive structures may be less clear than was previously thought.
Matrix remodeling; invadopodia; lamellipodia
Living cells are capable of extracting information from their environments and mounting appropriate responses to a variety of associated challenges. The underlying signal transduction networks enabling this can be quite complex, necessitating for their unraveling by sophisticated computational modeling coupled with precise experimentation. Although we are still at the beginning of this process, some recent examples of integrative analysis of cell signaling are very encouraging. This review highlights the case of the NF-κB pathway in order to illustrate how a quantitative model of a signaling pathway can be gradually constructed through continuous experimental validation, and what lessons one might learn from such exercises.
BCL-2 molecules are regulators of programmed cell death and defects in this pathway contribute to human diseases. One family member, MCL-1, is unique as its expression is tightly regulated and it is essential for promoting the survival of myriad cellular lineages. Additionally, MCL-1 promotes the maintenance of normal mitochondrial morphology and energy production. Dissection of these functions revealed recently that they depend on separate mitochondrial sub-localizations. MCL-1's anti-apoptotic activity is restricted to the outer mitochondrial membrane, whereas its function in mitochondrial physiology requires localization to the matrix. These findings provide an attractive model for how MCL-1's diverse functions may contribute to normal cell homeostasis and function. MCL-1 is highly amplified in human cancer suggesting that these functions may contribute to malignant cell growth and evasion of apoptosis.
Apoptosis; MCL-1; homeostasis; mitochondrial function; cancer; development
•EGF receptor endocytic traffic can regulate signaling and cell survival.•Signaling from activated EGFR occurs at the endosome as well as the cell surface.•Endocytosis can have positive and negative effects on signaling and tumorigenesis.•EGFR traffic promoted by antineoplastic therapy is important in tumor resistance.
The ligand-stimulated epidermal growth factor receptor (EGFR) has been extensively studied in the analysis of molecular mechanisms regulating endocytic traffic and the role of that traffic in signal transduction. Although such studies have largely focused on mitogenic signaling and dysregulated traffic in tumorigenesis, there is growing interest in the potential role of EGFR traffic in cell survival and the consequent response to cancer therapy. Here we review recent advances in our understanding of molecular mechanisms regulating ligand-stimulated EGFR activation, internalization, and post-endocytic sorting. The role of EGFR overexpression/mutation and new modulators of EGFR traffic in cancer and the response to cancer therapeutics are also discussed. Finally, we speculate on the relationship between EGFR traffic and cell survival.
epidermal growth factor receptor (EGFR); endocytosis; trafficking; ubiquitination; oncogenes; antineoplastic therapy
The complexity of the human body derives from numerous modular building blocks assembled hierarchically across multiple length scales. These building blocks, spanning sizes ranging from single cells to organs, interact to regulate development and normal organismal function but become disorganized during disease. Here, we review methods for the bottom-up and directed assembly of modular, multicellular, and tissue-like constructs in vitro. These engineered tissues will help refine our understanding of the relationship between form and function in the human body, provide new models for the breakdown in tissue architecture that accompanies disease, and serve as building blocks for the field of regenerative medicine.
Bottom-up; programmed assembly; tissue engineering; cell-cell nteractions; paracrine signaling
Synthetic biology re-imagines existing biological systems by designing and constructing new biological parts, devices, and systems. In the arena of cytoskeletal-based transport, synthetic approaches are currently used in two broad ways. First, molecular motors are harnessed for non-physiological functions in cells. Second, transport systems are engineered in vitro to determine the biophysical rules that govern motility. These rules are then applied to synthetic nanotechnological systems. We review recent advances in both of these areas and conclude by discussing future directions in engineering the cytoskeleton and its motors for transport.
dynein; kinesin; myosin; actin; microtubule; motor
Proteases are important for multiple processes during malignant progression including tumor angiogenesis, invasion and metastasis. Recent evidence reveals that tumor-promoting proteases function as part of an extensive multidirectional network of proteolytic interactions, in contrast to the unidirectional caspase cascade. These networks involve different constituents of the tumor microenvironment, and key proteases — such as cathepsin B, urokinase-type plasminogen activator and several matrix metalloproteinases — occupy central nodes for amplifying proteolytic signals passing through the network. The proteolytic network interacts with other important signaling pathways in tumor biology, involving chemokines, cytokines, and kinases. Viewing these proteolytic interactions as a system of activating and inhibiting reactions provides insight into tumor biology and reveals relevant pharmaceutical targets. This review will examine recent advances in understanding proteases in cancer, and summarize how their network of activity is co-opted to promote tumor progression.
protease; inhibitor; invasion; metastasis; tumor microenvironment; cascade
The formation of skeletal muscle is a tightly regulated process that is critically modulated by Wnt signaling. Myogenesis is dependent on the precise and dynamic integration of multiple Wnt signals allowing for self-renewal and progression of muscle precursors in the myogenic lineage. Dis-regulation of Wnt signaling can lead to severe developmental defects and perturbation of muscle homeostasis. Recent work has revealed novel roles of the non-canonical planar-cell-polarity (PCP) and AKT/mTOR pathways in mediating the effects of Wnt on skeletal muscle. In this review, we discuss the role of Wnt signaling in myogenesis and in regulating the homeostasis of adult muscle.
Wnt; Frizzled; myogenesis; skeletal muscle; satellite cell; myofiber
Changes in cell homeostasis, or cell ‘stress’, are thought to tax the ability of the Hsp90 chaperone to facilitate an array of processes critical for genome maintenance. Here, we review the current understanding of how Hsp90 chaperone machinery ensures the function of proteins important for DNA repair, recombination and chromosome segregation. We discuss the idea that cell ‘stress’ can overload Hsp90, resulting in genomic instability that may have important implications for stress adaptation and selection. The importance of Hsp90 in genome maintenance and its limited capacity to buffer the proteome may underlie the initiation or progression of diseases such as cancer.
Hsp90; chaperone; cell stress; genome instability; adaptation
The stereotypical function of kinesin superfamily motors is to transport cargo along microtubules. However, some kinesins also shape the microtubule track by regulating microtubule assembly and disassembly. Recent work has shown that the kinesin-8 family of motors are key regulators of cellular microtubule length. The studied kinesin-8s are highly processive motors that walk towards the microtubule plus-end. Once at plus-ends, they have complex effects on polymer dynamics: kinesin-8s either destabilize or stabilize microtubules, depending on the context. This review will focus on the mechanisms underlying kinesin-8-microtubule interactions and microtubule length control. We will compare and contrast kinesin-8s with the other major microtubule-regulating kinesins (kinesin-4 and kinesin-13), to survey the current understanding of the diverse ways that kinesins control microtubule dynamics.
kinesin-8; kinesin-13; kinesin-4; microtubule dynamics; microtubule depolymerase
Cells die by a variety of mechanisms, only some of which have been elucidated in detail. A number of `active' forms of cell death exist in which the cell participates in its own death, including apoptosis, programmed necrosis, mitotic catastrophe, and the recently described ferroptosis, among other processes. Here, we attempt to explain why there are so many different forms of cell death, and propose a distinction between active death that is `suicide' versus `sabotage.'
Herpesvirus capsids traverse the nuclear envelope by utilizing an unusual export pathway termed nuclear egress. In this process, the viral capsid is delivered into the perinuclear space, producing a vesicular intermediate after fission. After fusion with the outer nuclear membrane, the naked capsid is released into the cytosol. A recent study now suggests that this pathway might be an endogenous cellular pathway, co-opted by viruses, that serves to transport cellular cargo exceeding the size limit imposed by the nuclear pore complex. We propose that one function of this pathway is to transport nuclear protein aggregates to the cytosolic autophagy machinery. Our model has implications for our understanding of laminopathies and related diseases affecting proteins residing at the inner nuclear membrane and nuclear lamina.
Torsin A; LINC complex; chaperones; nuclear envelope; egress of nuclear aggregates (EGNA); premature aging
It is widely believed that calorie restriction (CR) can extend the lifespan of model organisms and protect against aging-related diseases. A potential CR mimetic is resveratrol, which may have beneficial effects against numerous diseases such as type 2 diabetes, cardiovascular diseases, and cancer in tissue culture and animal models. However, resveratrol in its current form is not ideal as therapy, because even at very high doses it has modest efficacy and many downstream effects. Identifying the cellular targets responsible for the effects of resveratrol and developing target-specific therapies will be helpful in increasing the efficacy of this drug without increasing its potential adverse effects. A recent discovery suggests that the metabolic effects of resveratrol may be mediated by inhibiting cAMP phosphodiesterases (PDEs), particularly PDE4. Here, we review the current literature on the metabolic and cardiovascular effects of resveratrol and attempt to shed light on the controversies surrounding its action.
resveratrol; PDE; AMPK; Sirt1; calorie restriction; diabetes
There is mounting evidence that the plasma membrane is highly dynamic and organized in a complex manner. The cortical cytoskeleton is proving to be a particularly important regulator of plasmalemmal organization, modulating the mobility of proteins and lipids in the membrane, facilitating their segregation and influencing their clustering. This organization plays a critical role in receptor-mediated signaling, especially in the case of immunoreceptors, which require lateral clustering for their activation. Based on recent developments, we discuss the structures and mechanisms whereby the cortical cytoskeleton regulates membrane dynamics and organization, and how the non-uniform distribution of immunoreceptors and their self-association may affect activation and signaling.
membrane domain; receptor clustering; immunoreceptor signaling; membrane skeleton; rafts; cytoskeleton
Mitochondria adopt a variety of different shapes in eukaryotic cells, ranging from multiple, small compartments to elaborate tubular networks. The establishment and maintenance of different mitochondrial morphologies depends, in part, on the equilibrium between opposing fission and fusion events. Recent studies in yeast, flies, worms and mammalian cells indicate that three high-molecular-weight GTPases control mitochondrial membrane dynamics. One of these is a dynamin-related GTPase that acts on the outer mitochondrial membrane to regulate fission. Recently, genetic approaches in budding yeast have identified additional components of the fission machinery. These and other new findings suggest a common mechanism for membrane fission events that has been conserved and adapted during eukaryotic evolution.