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1.  DNA Repair by Reversal of DNA Damage 
doi:10.1101/cshperspect.a023440
PMCID: PMC3970413
3.  Tie2 and Eph Receptor Tyrosine Kinase Activation and Signaling 
Cold Spring Harbor perspectives in biology  2014;6(3):10.1101/cshperspect.a009142 a009142.
The Eph and Tie cell surface receptors mediate a variety of signaling events during development and in the adult organism. As other receptor tyrosine kinases, they are activated on binding of extracellular ligands and their catalytic activity is tightly regulated on multiple levels. The Eph and Tie receptors display some unique characteristics, including the requirement of ligand-induced receptor clustering for efficient signaling. Interestingly, both Ephs and Ties can mediate different, even opposite, biological effects depending on the specific ligand eliciting the response and on the cellular context. Here we discuss the structural features of these receptors, their interactions with various ligands, as well as functional implications for downstream signaling initiation. The Eph/ephrin structures are already well reviewed and we only provide a brief overview on the initial binding events. We go into more detail discussing the Tie-angiopoietin structures and recognition.
doi:10.1101/cshperspect.a009142
PMCID: PMC3949358  PMID: 24478383
4.  Multiple Functions of BCL-2 Family Proteins 
BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
Pro- and antiapoptotic BCL-2 family proteins have critical roles in normal cell physiology. These proteins have a characteristic shape and may harbor a common biochemical function not yet discovered.
doi:10.1101/cshperspect.a008722
PMCID: PMC3552500  PMID: 23378584
5.  Inhibitor of Apoptosis (IAP) Proteins–Modulators of Cell Death and Inflammation 
Misregulated innate immune signaling and cell death form the basis of much human disease pathogenesis. Inhibitor of apoptosis (IAP) protein family members are frequently overexpressed in cancer and contribute to tumor cell survival, chemo-resistance, disease progression, and poor prognosis. Although best known for their ability to regulate caspases, IAPs also influence ubiquitin (Ub)-dependent pathways that modulate innate immune signaling via activation of nuclear factor κB (NF-κB). Recent research into IAP biology has unearthed unexpected roles for this group of proteins. In addition, the advances in our understanding of the molecular mechanisms that IAPs use to regulate cell death and innate immune responses have provided new insights into disease states and suggested novel intervention strategies. Here we review the functions assigned to those IAP proteins that act at the intersection of cell death regulation and inflammatory signaling.
IAPs inhibit caspases and cell death. They also control ubiquitin-dependent pathways that regulate activation of NF-κB and MAPK, which drive the expression of genes involved in inflammation and cell survival.
doi:10.1101/cshperspect.a008730
PMCID: PMC3552501  PMID: 23378585
6.  Tinkering with Translation: Protein Synthesis in Virus-Infected Cells 
Viruses are obligate intracellular parasites, and their replication requires host cell functions. Although the size, composition, complexity, and functions encoded by their genomes are remarkably diverse, all viruses rely absolutely on the protein synthesis machinery of their host cells. Lacking their own translational apparatus, they must recruit cellular ribosomes in order to translate viral mRNAs and produce the protein products required for their replication. In addition, there are other constraints on viral protein production. Crucially, host innate defenses and stress responses capable of inactivating the translation machinery must be effectively neutralized. Furthermore, the limited coding capacity of the viral genome needs to be used optimally. These demands have resulted in complex interactions between virus and host that exploit ostensibly virus-specific mechanisms and, at the same time, illuminate the functioning of the cellular protein synthesis apparatus.
Viruses commandeer and control translation in the host cell. Mechanisms range from manipulating key translation factors to using cis-acting elements that recruit ribosomes or modify genome-coding capacity.
doi:10.1101/cshperspect.a012351
PMCID: PMC3579402  PMID: 23209131
7.  The β-Catenin Destruction Complex 
The Wnt/β-catenin pathway is highly regulated to insure the correct temporal and spatial activation of its target genes. In the absence of a Wnt stimulus, the transcriptional coactivator β-catenin is degraded by a multiprotein “destruction complex” that includes the tumor suppressors Axin and adenomatous polyposis coli (APC), the Ser/Thr kinases GSK-3 and CK1, protein phosphatase 2A (PP2A), and the E3-ubiquitin ligase β-TrCP. The complex generates a β-TrCP recognition site by phosphorylation of a conserved Ser/Thr-rich sequence near the β-catenin amino terminus, a process that requires scaffolding of the kinases and β-catenin by Axin. Ubiquitinated β-catenin is degraded by the proteasome. The molecular mechanisms that underlie several aspects of destruction complex function are poorly understood, particularly the role of APC. Here we review the molecular mechanisms of destruction complex function and discuss several potential roles of APC in β-catenin destruction.
β-Catenin is degraded in the absence of a Wnt stimulus. Although the functions of the core components of the multiprotein β-catenin destruction complex are generally known, the role of APC is unclear.
doi:10.1101/cshperspect.a007898
PMCID: PMC3579403  PMID: 23169527
8.  Wnt Signaling in Vertebrate Axis Specification 
The Wnt pathway is a major embryonic signaling pathway that controls cell proliferation, cell fate, and body-axis determination in vertebrate embryos. Soon after egg fertilization, Wnt pathway components play a role in microtubule-dependent dorsoventral axis specification. Later in embryogenesis, another conserved function of the pathway is to specify the anteroposterior axis. The dual role of Wnt signaling in Xenopus and zebrafish embryos is regulated at different developmental stages by distinct sets of Wnt target genes. This review highlights recent progress in the discrimination of different signaling branches and the identification of specific pathway targets during vertebrate axial development.
Wnt signaling plays a dual role in vertebrate axis specification. It helps specify the dorsoventral axis soon after egg fertilization and the anteroposterior axis later in embryogenesis.
doi:10.1101/cshperspect.a007955
PMCID: PMC3579404  PMID: 22914799
9.  Altered Sulfide (H2S) Metabolism in Ethylmalonic Encephalopathy 
Hydrogen sulfide (sulfide, H2S) is a colorless, water-soluble gas with a typical smell of rotten eggs. In the past, it has been investigated for its role as a potent toxic gas emanating from sewers and swamps or as a by-product of industrial processes. At high concentrations, H2S is a powerful inhibitor of cytochrome c oxidase; in trace amounts, it is an important signaling molecule, like nitric oxide (NO) and carbon monoxide (CO), together termed “gasotransmitters.” This review will cover the physiological role and the pathogenic effects of H2S, focusing on ethylmalonic encephalopathy, a human mitochondrial disorder caused by genetic abnormalities of sulfide metabolism. We will also discuss the options that are now conceivable for preventing genetically driven chronic H2S toxicity, taking into account that a complete understanding of the physiopathology of H2S has still to be achieved.
In ethylmalonic encephalopathy, sulfide intermediates are not degraded properly. Sulfides build up and inhibit cytochrome c oxidase, the last enzyme in the mitochondrial electron-transport chain.
doi:10.1101/cshperspect.a011437
PMCID: PMC3579397  PMID: 23284046
10.  Endoreplication 
Developmentally programmed polyploidy occurs by at least four different mechanisms, two of which (endoreduplication and endomitosis) involve switching from mitotic cell cycles to endocycles by the selective loss of mitotic cyclin-dependent kinase (CDK) activity and bypassing many of the processes of mitosis. Here we review the mechanisms of endoreplication, focusing on recent results from Drosophila and mice.
A single polyploid nucleus is produced when a cell undergoes multiple S phases without entering mitosis. This process of endoreplication is similar in mammals, insects, and plants, although there are species-specific differences.
doi:10.1101/cshperspect.a012948
PMCID: PMC3579398  PMID: 23284048
11.  Clearing the Dead: Apoptotic Cell Sensing, Recognition, Engulfment, and Digestion 
Clearance of apoptotic cells is the final stage of programmed cell death. Uncleared corpses can become secondarily necrotic, promoting inflammation and autoimmunity. Remarkably, even in tissues with high cellular turnover, apoptotic cells are rarely seen because of efficient clearance mechanisms in healthy individuals. Recently, significant progress has been made in understanding the steps involved in prompt cell clearance in vivo. These include the sensing of corpses via “find me” signals, the recognition of corpses via “eat me” signals and their cognate receptors, the signaling pathways that regulate cytoskeletal rearrangement necessary for engulfment, and the responses of the phagocyte that keep cell clearance events “immunologically silent.” This study focuses on our understanding of these steps.
Phagocytes recognize dead cells through “find me” (e.g., fractalkine) and “eat me” (e.g., phosphatidylserine) signals. Signaling events within phagocytes then control the internalization and digestion of the dead cells.
doi:10.1101/cshperspect.a008748
PMCID: PMC3579390  PMID: 23284042
12.  Replication of Epstein–Barr Viral DNA 
Epstein–Barr virus (EBV) is a paradigm for human tumor viruses: it is the first virus recognized to cause cancer in people; it causes both lymphomas and carcinomas; yet these tumors arise infrequently given that most people in the world are infected with the virus. EBV is maintained extrachromosomally in infected normal and tumor cells. Eighty-four percent of these viral plasmids replicate each S phase, are licensed, require a single viral protein for their synthesis, and can use two functionally distinct origins of DNA replication, oriP, and Raji ori. Eighty-eight percent of newly synthesized plasmids are segregated faithfully to the daughter cells. Infectious viral particles are not synthesized under these conditions of latent infection. This plasmid replication is consistent with survival of EBV’s host cells. Rare cells in an infected population either spontaneously or following exogenous induction support EBV’s lytic cycle, which is lethal for the cell. In this case, the viral DNA replicates 100-fold or more, uses a third kind of viral origin of DNA replication, oriLyt, and many viral proteins. Here we shall describe the three modes of EBV’s replication as a function of the viral origins used and the viral and cellular proteins that mediate the DNA synthesis from these origins focusing, where practical, on recent advances in our understanding.
Epstein–Barr virus has infected more than 6.5 billion people in the world. It has distinct modes of replication.
doi:10.1101/cshperspect.a013029
PMCID: PMC3579399  PMID: 23284049
13.  Toll-Like Receptor Signaling 
Toll-like receptors sense pathogen-associated molecular patterns (e.g., lipopolysaccharides) and trigger gene-expression changes that ultimately eradicate the invading microbes.
doi:10.1101/cshperspect.a011247
PMCID: PMC3579400  PMID: 23284045
14.  Toward a Genome-Wide Landscape of Translational Control 
Genome-wide analysis of translational control has taken strides in recent years owing to the advent of high-throughput technologies, including DNA microarrays and deep sequencing. Global studies have unraveled a principal role, among posttranscriptional mechanisms, for mRNA translation in determining protein levels in the cell. The impact of translational control in dynamic regulation of the proteome under different conditions is increasingly appreciated. Here we review genome-wide studies that use high-throughput techniques and bioinformatics to assess the role of mRNA translation in the regulation of protein levels; we also discuss how genome-wide data on mRNA translation can be obtained, analyzed, and used to identify mechanisms of translational control.
High-throughput technologies and bioinformatics tools have revealed how translational control mechanisms substantially affect gene expression and protein levels on a global scale.
doi:10.1101/cshperspect.a012302
PMCID: PMC3579401  PMID: 23209130
15.  The Endolysosomal System in Cell Death and Survival 
The endocytic pathway is a system specialized for the uptake of compounds from the cell microenvironment for their degradation. It contains an arsenal of hydrolases, including proteases, which are normally enclosed in membrane-bound organelles, but if released to the cytosol can initiate apoptosis signaling pathways. Endogenous and exogenous compounds have been identified that can mediate destabilization of lysosomal membranes, and it was shown that lysosomal proteases are not only able to initiate apoptotic signaling but can also amplify the apoptotic pathways initiated in other cellular compartments. The endocytic pathway also receives cargo destined for degradation via the autophagic pathway. By recycling energy and biosynthetic substrates, and by degrading damaged organelles and molecules, the endocytic system assists the autophagic system in resisting apoptotic stimuli. Steps leading to lysosomal membrane permeabilization and subsequent triggering of cell death as well as the therapeutic potential of intervention in lysosomal membrane permeabilization will be discussed.
If lysosomal membranes are disturbed, the hydrolases released into the cytosol can initiate apoptosis. Harnessing or interfering with the lysosomal apoptotic pathway may have therapeutic potential (e.g., in cancer).
doi:10.1101/cshperspect.a008755
PMCID: PMC3579391  PMID: 23284043
16.  DNA Repair by Reversal of DNA Damage 
Endogenous and exogenous factors constantly challenge cellular DNA, generating cytotoxic and/or mutagenic DNA adducts. As a result, organisms have evolved different mechanisms to defend against the deleterious effects of DNA damage. Among these diverse repair pathways, direct DNA-repair systems provide cells with simple yet efficient solutions to reverse covalent DNA adducts. In this review, we focus on recent advances in the field of direct DNA repair, namely, photolyase-, alkyltransferase-, and dioxygenase-mediated repair processes. We present specific examples to describe new findings of known enzymes and appealing discoveries of new proteins. At the end of this article, we also briefly discuss the influence of direct DNA repair on other fields of biology and its implication on the discovery of new biology.
Simple direct repair mechanisms can fix DNA damage without breaking the DNA backbone. These essentially error-free processes include photolyase-, alkyltransferase-, and dioxygenase-mediated mechanisms.
doi:10.1101/cshperspect.a012575
PMCID: PMC3579392  PMID: 23284047
17.  How Viruses Use the Endoplasmic Reticulum for Entry, Replication, and Assembly 
To cause infection, a virus enters a host cell, replicates, and assembles, with the resulting new viral progeny typically released into the extracellular environment to initiate a new infection round. Virus entry, replication, and assembly are dynamic and coordinated processes that require precise interactions with host components, often within and surrounding a defined subcellular compartment. Accumulating evidence pinpoints the endoplasmic reticulum (ER) as a crucial organelle supporting viral entry, replication, and assembly. This review focuses on the molecular mechanism by which different viruses co-opt the ER to accomplish these crucial infection steps. Certain bacterial toxins also hijack the ER for entry. An interdisciplinary approach, using rigorous biochemical and cell biological assays coupled with advanced microscopy strategies, will push to the next level our understanding of the virus-ER interaction during infection.
An ideal conduit for certain viruses to enter the cytosol is the ER-to-cytosol retro-translocation machinery in the ER. Furthermore, budding at the ER membrane plays a role during viral replication and assembly.
doi:10.1101/cshperspect.a013250
PMCID: PMC3579393  PMID: 23284050
18.  Cell Biology of the Endoplasmic Reticulum and the Golgi Apparatus through Proteomics 
Enriched endoplasmic reticulum (ER) and Golgi membranes subjected to mass spectrometry have uncovered over a thousand different proteins assigned to the ER and Golgi apparatus of rat liver. This, in turn, led to the uncovering of several hundred proteins of poorly understood function and, through hierarchical clustering, showed that proteins distributed in patterns suggestive of microdomains in cognate organelles. This has led to new insights with respect to their intracellular localization and function. Another outcome has been the critical testing of the cisternal maturation hypothesis showing overwhelming support for a predominant role of COPI vesicles in the transport of resident proteins of the ER and Golgi apparatus (as opposed to biosynthetic cargo). Here we will discuss new insights gained and also highlight new avenues undertaken to further explore the cell biology of the ER and the Golgi apparatus through tandem mass spectrometry.
The Golgi and ER are temporally and spatially linked. Mass spectrometry and hierarchical clustering algorithms offer new insights into the localization and function of their proteins.
doi:10.1101/cshperspect.a015073
PMCID: PMC3579394  PMID: 23284051
19.  Development of the Endochondral Skeleton 
Much of the mammalian skeleton is composed of bones that originate from cartilage templates through endochondral ossification. Elucidating the mechanisms that control endochondral bone development is critical for understanding human skeletal diseases, injury response, and aging. Mouse genetic studies in the past 15 years have provided unprecedented insights about molecules regulating chondrocyte formation, chondrocyte maturation, and osteoblast differentiation, all key processes of endochondral bone development. These include the roles of the secreted proteins IHH, PTHrP, BMPs, WNTs, and FGFs, their receptors, and transcription factors such as SOX9, RUNX2, and OSX, in regulating chondrocyte and osteoblast biology. This review aims to integrate the known functions of extracellular signals and transcription factors that regulate development of the endochondral skeleton.
Endochondral ossification produces bone via a cartilage intermediate. Key extracellular signals (e.g., bone morphogenetic proteins), their receptors, and transcription factors (e.g., SOX9) are essential for this process.
doi:10.1101/cshperspect.a008334
PMCID: PMC3579395  PMID: 23284041
20.  Where Killers Meet—Permeabilization of the Outer Mitochondrial Membrane during Apoptosis 
Although mitochondria are usually considered as supporters of life, they are also involved in cellular death. Mitochondrial outer membrane permeabilization (MOMP) is a crucial event during apoptosis because it causes the release of proapoptotic factors from the mitochondrial intermembrane space to the cytosol. MOMP is mainly controlled by the Bcl-2 family of proteins, which consists of both proapoptotic and antiapoptotic members. We discuss the current understanding of how activating and inhibitory interactions within this family lead to the activation and oligomerization of MOMP effectors Bax and Bak, which result in membrane permeabilization. The order of events leading to MOMP is then highlighted step by step, emphasizing recent discoveries regarding the formation of Bax/Bak pores on the outer mitochondrial membrane. Besides the Bcl-2 proteins, the mitochondrial organelle contributes to and possibly regulates MOMP, because mitochondrial resident proteins and membrane lipids are prominently involved in the process.
During apoptosis, mitochondrial outer membrane permeabilization (MOMP) causes the activation of proapoptotic effectors (Bax and Bak). It is controlled by Bcl-2 family members and possibly mitochondrial factors.
doi:10.1101/cshperspect.a011106
PMCID: PMC3579396  PMID: 23284044
21.  mTOR-Dependent Cell Survival Mechanisms 
The mechanistic target of rapamycin (mTOR) kinase is a conserved regulator of cell growth, proliferation, and survival. In cells, mTOR is the catalytic subunit of two complexes called mTORC1 and mTORC2, which have distinct upstream regulatory signals and downstream substrates. mTORC1 directly senses cellular nutrient availability while indirectly sensing circulating nutrients through growth factor signaling pathways. Cellular stresses that restrict growth also impinge on mTORC1 activity. mTORC2 is less well understood and appears only to sense growth factors. As an integrator of diverse growth regulatory signals, mTOR evolved to be a central signaling hub for controlling cellular metabolism and energy homoeostasis, and defects in mTOR signaling are important in the pathologies of cancer, diabetes, and aging. Here we discuss mechanisms by which each mTOR complex might regulate cell survival in response to metabolic and other stresses.
mTOR is a signaling hub for cell metabolism. It serves as a point of convergence between a nutrient-sensing pathway and PI3K–AKT signaling (i.e., as part of mTORC1) and as a regulator of AKT itself (i.e., as part of mTORC2).
doi:10.1101/cshperspect.a008771
PMCID: PMC3504431  PMID: 23124837
22.  Oncogenes in Cell Survival and Cell Death 
The transforming effects of proto-oncogenes such as MYC that mediate unrestrained cell proliferation are countered by “intrinsic tumor suppressor mechanisms” that most often trigger apoptosis. Therefore, cooperating genetic or epigenetic effects to suppress apoptosis (e.g., overexpression of BCL2) are required to enable the dual transforming processes of unbridled cell proliferation and robust suppression of apoptosis. Certain oncogenes such as BCR-ABL are capable of concomitantly mediating the inhibition of apoptosis and driving cell proliferation and therefore are less reliant on cooperating lesions for transformation. Accordingly, direct targeting of BCR-ABL through agents such as imatinib have profound antitumor effects. Other oncoproteins such as MYC rely on the anti-apoptotic effects of cooperating oncoproteins such as BCL2 to facilitate tumorigenesis. In these circumstances, where the primary oncogenic driver (e.g., MYC) cannot yet be therapeutically targeted, inhibition of the activity of the cooperating antiapoptotic protein (e.g., BCL2) can be exploited for therapeutic benefit.
Some proto-oncogenes (e.g., BCR-ABL) induce both cell proliferation and the suppression of apoptosis. Others (e.g., MYC) must circumvent apoptotic mechanisms for tumorigenesis to occur.
doi:10.1101/cshperspect.a009829
PMCID: PMC3504432  PMID: 23209150
23.  Diseases Associated with Defective Responses to DNA Damage 
Within the last decade, multiple novel congenital human disorders have been described with genetic defects in known and/or novel components of several well-known DNA repair and damage response pathways. Examples include disorders of impaired nucleotide excision repair, DNA double-strand and single-strand break repair, as well as compromised DNA damage-induced signal transduction including phosphorylation and ubiquitination. These conditions further reinforce the importance of multiple genome stability pathways for health and development in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanics of genome stability and in some cases provide potential routes to help exploit these pathways therapeutically. Here, I will review a selection of these exciting findings from the perspective of the disorders themselves, describing how they were identified, how genotype informs phenotype, and how these defects contribute to our growing understanding of genome stability pathways.
Many human disorders are associated with genetic defects in DNA repair and damage response pathways. For example, ataxia telangiectasia is caused by defects in ATM, which is responsible for repairing double-stranded breaks in DNA.
doi:10.1101/cshperspect.a012773
PMCID: PMC3504433  PMID: 23209155
24.  Protein-Folding Homeostasis in the Endoplasmic Reticulum and Nutritional Regulation 
The flux of newly synthesized proteins entering the endoplasmic reticulum (ER) is under negative regulation by the ER-localized PKR-like ER kinase (PERK). PERK is activated by unfolded protein stress in the ER lumen and inhibits new protein synthesis by the phosphorylation of translation initiation factor eIF2α. This homeostatic mechanism, shared by all animal cells, has proven to be especially important to the well-being of professional secretory cells, notably the endocrine pancreas. PERK, its downstream effectors, and the allied branches of the unfolded protein response intersect broadly with signaling pathways that regulate nutrient assimilation, and ER stress and the response to it have been implicated in the development of the metabolic syndrome accompanying obesity in mammals. Here we review our current understanding of the cell biology underlying these relationships.
PERK, activated by unfolded protein stress in the ER, inhibits the synthesis of new proteins. This homeostatic mechanism is especially important in pancreatic β cells, which produce insulin.
doi:10.1101/cshperspect.a013177
PMCID: PMC3504434  PMID: 23209157
25.  The Endoplasmic Reticulum-Associated Degradation Pathways of Budding Yeast 
Protein misfolding is a common cellular event that can produce intrinsically harmful products. To reduce the risk, quality control mechanisms are deployed to detect and eliminate misfolded, aggregated, and unassembled proteins. In the secretory pathway, it is mainly the endoplasmic reticulum-associated degradation (ERAD) pathways that perform this role. Here, specialized factors are organized to monitor and process the folded states of nascent polypeptides. Despite the complex structures, topologies, and posttranslational modifications of client molecules, the ER mechanisms are the best understood among all protein quality-control systems. This is the result of convergent and sometimes serendipitous discoveries by researchers from diverse fields. Although major advances in ER quality control and ERAD came from all model organisms, this review will focus on the discoveries culminating from the simple budding yeast.
In budding yeast, two main ER membrane-embedded complexes (Hrd1 and Doa10) recognize, translocate, and ubiquitinate misfolded proteins for degradation. Many other factors support this process.
doi:10.1101/cshperspect.a013193
PMCID: PMC3504435  PMID: 23209158

Results 1-25 (582)