Abstract:
:Signaling pathways control cell fate decisions that ultimately determine the behavior of cancer cells. Therefore, the dynamics of pathway activity may contain prognostically relevant information different from that contained in the static nature of other types of biomarkers. To investigate this hypothesis, we characterized the network that regulated stress signaling by the c-Jun N-terminal kinase (JNK) pathway in neuroblastoma cells. We generated an experimentally calibrated and validated computational model of this network and used the model to extract prognostic information from neuroblastoma patient-specific simulations of JNK activation. Switch-like JNK activation mediates cell death by apoptosis. An inability to initiate switch-like JNK activation in the simulations was significantly associated with poor overall survival for patients with neuroblastoma with or without MYCN amplification, indicating that patient-specific simulations of JNK activation could stratify patients. Furthermore, our analysis demonstrated that extracting information about a signaling pathway to develop a prognostically useful model requires understanding of not only components and disease-associated changes in the abundance or activity of the components but also how those changes affect pathway dynamics.
journal_name
Sci Signaljournal_title
Science signalingauthors
Fey D,Halasz M,Dreidax D,Kennedy SP,Hastings JF,Rauch N,Munoz AG,Pilkington R,Fischer M,Westermann F,Kolch W,Kholodenko BN,Croucher DRdoi
10.1126/scisignal.aab0990subject
Has Abstractpub_date
2015-12-22 00:00:00pages
ra130issue
408eissn
1945-0877issn
1937-9145pii
8/408/ra130journal_volume
8pub_type
杂志文章abstract::Cancer cells acquire resistance to DNA-damaging therapeutic agents, such as cisplatin, but the genetic mechanisms through which this occurs remain unclear. We show that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of the c-MYC inhibitor BIN1 (bridging integrator 1). The sensitivity of ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2001556
更新日期:2011-03-29 00:00:00
abstract::The TRAF [tumor necrosis factor receptor-associated factor] family of cytoplasmic adaptor proteins link cell-surface receptors to intracellular signaling pathways that regulate innate and adaptive immune responses. In response to activation of RIG-I (retinoic acid-inducible gene I), a component of a pattern recognitio...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2003152
更新日期:2012-11-13 00:00:00
abstract::The scattering of cultured epithelial cells in response to hepatocyte growth factor (HGF) is a model system that recapitulates key features of metastatic cell behavior in vitro, including disruption of cell-cell adhesions and induction of cell migration. We have developed image analysis tools that do not require fluor...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2002677
更新日期:2012-07-03 00:00:00
abstract::Pentraxin 3 (PTX3), a member of the long pentraxin subfamily within the family of pentraxins, is a soluble pattern recognition molecule that functions in the innate immune system. Innate immunity affords the infected host protection against sepsis, a potentially life-threatening inflammatory response to infection. Ext...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2005522
更新日期:2014-09-16 00:00:00
abstract::Genetically encoded fluorescent sensors enable cell-specific measurements of ions and small molecules in real time. Cyclic adenosine monophosphate (cAMP) is one of the most important signaling molecules in virtually all cell types and organisms. We describe cAMPr, a new single-wavelength cAMP sensor. We developed cAMP...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aah3738
更新日期:2018-03-06 00:00:00
abstract::The mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 2 (ERK2) is ubiquitously expressed in mammalian tissues and is involved in a wide range of biological processes. Although MAPKs have been intensely studied, identification of their substrates remains challenging. We have optimized a chem...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2002010
更新日期:2011-10-25 00:00:00
abstract::Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development through VEGF receptors (VEGFRs). The VEGFR immunoglobulin homology domain 2 (D2) is critical for ligand binding, and D3 provides additional interaction sites. VEGF-B and placenta growth factor (PlGF) bind to VEGFR-1 with high a...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2003905
更新日期:2013-07-02 00:00:00
abstract::Notch signaling is used to choose cell fates in many developmental contexts. New evidence shows that circulating blood cells in Drosophila, in the absence of Notch ligand provided by neighboring cells, activate Notch signaling through stabilization with the hypoxia-inducible factor-α (HIF-α) transcription factor. Alth...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.2002277
更新日期:2011-07-12 00:00:00
abstract::This two-issue series focuses on how understanding how signaling pathways are altered in cancer cells can enable researchers to develop more effective therapies. Cancer is a pleiotropic disease. Tumor cells change over time and, even within a specific tumor, cells may have different mutations and dependencies on diffe...
journal_title:Science signaling
pub_type: 社论
doi:10.1126/scisignal.2004149
更新日期:2013-03-26 00:00:00
abstract::Morphogens form concentration gradients that organize patterns of cells and control growth. It has been suggested that, rather than the intensity of morphogen signaling, it is its gradation that is the relevant modulator of cell proliferation. According to this view, the ability of morphogens to regulate growth during...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2000360
更新日期:2009-10-06 00:00:00
abstract::Under drought stress, abscisic acid (ABA) triggers closure of leaf cell pores called stomata, which are formed by two specialized cells called guard cells in plant epidermis. Two pathways downstream of ABA stimulate phosphorylation of the S-type anion channels SLAC1 (slow anion channel associated 1) and SLAH3 (SLAC1 h...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2005703
更新日期:2014-09-09 00:00:00
abstract::Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of s...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.abd8379
更新日期:2020-12-22 00:00:00
abstract::Premature labor and consequent neonatal mortality may be prevented by stimulating the expression of PIBF1 in uterine B cells. ...
journal_title:Science signaling
pub_type: 评论,杂志文章
doi:10.1126/scisignal.aam7592
更新日期:2017-01-17 00:00:00
abstract::Teaching the practical aspects of signal transduction to large undergraduate classes can be challenging when there is only a finite time frame in which to engage in laboratory activities. This teaching resource describes the use of bead-based ALPHAscreen technology for a class of 300 second-year biochemistry students,...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.262tr1
更新日期:2009-03-17 00:00:00
abstract::The LKB1 serine-threonine kinase is a tumor suppressor that is inactivated in a large number of sporadic human lung non-small cell carcinomas (NSCLCs) and cervical cancers. Genetic deletion of LKB1 in various mouse tissues results in tumorigenesis, and loss of LKB1 increases metastasis in a mouse model of NSCLC. LKB1 ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.286pe55
更新日期:2009-09-01 00:00:00
abstract::The role of mucin 1 (MUC1) in protecting epithelia from microbial infection, enzymatic digestion, and other irritants has been appreciated for some time. In addition, MUC1 serves as a barrier to embryo implantation. MUC1 is highly abundant in many tumors in which its role in barrier function may serve to protect cells...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.127pe35
更新日期:2008-07-08 00:00:00
abstract::The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)-producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue r...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aav3048
更新日期:2019-05-21 00:00:00
abstract::Intracellular calcium (Ca2+) signals are of prime importance for cellular function and behavior and are underpinned by a plethora of Ca2+ channels, pumps, transporters, and binding proteins that are regulated in complex ways. A series of biennial meetings, the International Meetings of the European Calcium Society (EC...
journal_title:Science signaling
pub_type:
doi:10.1126/scisignal.aaz0961
更新日期:2019-09-17 00:00:00
abstract::Signaling by the transforming growth factor-β (TGF-β) receptors I and II (TβRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ce...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aam7464
更新日期:2017-10-24 00:00:00
abstract::Store-operated Ca2+ entry (SOCE) is critical for salivary gland fluid secretion. We report that radiation treatment caused persistent salivary gland dysfunction by activating a TRPM2-dependent mitochondrial pathway, leading to caspase-3-mediated cleavage of stromal interaction molecule 1 (STIM1) and loss of SOCE. Afte...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aal4064
更新日期:2017-06-06 00:00:00
abstract::The postsynaptic site of neurons is composed of more than 1500 proteins arranged in protein-protein interaction complexes, the composition of which is modulated by protein phosphorylation through the actions of complex signaling networks. Components of these networks function as key regulators of synaptic plasticity, ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aaf6716
更新日期:2016-08-09 00:00:00
abstract::Mutations in AMPA receptor recycling machinery underlie cognitive impairment in an intellectual disorder and in neurodegenerative diseases. ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aan5454
更新日期:2017-05-02 00:00:00
abstract::The capacity of a rabies virus to promote neuronal survival (a signature of virulence) or death (a marker of attenuation) depends on the cellular partners recruited by the PDZ-binding site (PDZ-BS) of its envelope glycoprotein (G). Neuronal survival requires the selective association of the PDZ-BS of G with the PDZ do...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.2000510
更新日期:2010-01-19 00:00:00
abstract::Mineralocorticoid receptor (MR) antagonists are effective at treating heart failure. In this issue of Science Signaling, Oakley et al. provide new insight into their cardioprotective actions and highlight the importance of the opposing relationship between the MR and the related glucocorticoid receptor (GR) in the res...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.aaw8715
更新日期:2019-04-16 00:00:00
abstract::Parkinson's disease (PD) is a neurodegenerative disorder in which the loss of dopaminergic neurons in the midbrain (mDA neurons) causes progressive loss of motor control and function. Using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells, we investigated the mechanisms ...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aal4165
更新日期:2017-08-22 00:00:00
abstract::The K+/Cl- cotransporter KCC2 is a molecular switch between excitatory and inhibitory effects of GABAergic inputs into neurons. In a pair of exciting studies, Watanabe et al. and Pisella et al. elucidate the role of KCC2 dephosphorylation in this process and reveal its consequences for neurodevelopment and nervous sys...
journal_title:Science signaling
pub_type: 评论,杂志文章,评审
doi:10.1126/scisignal.aay8960
更新日期:2019-10-15 00:00:00
abstract::This two-part lecture introduces students to the scientific computing language MATLAB. Prior computer programming experience is not required. The lectures present basic concepts of computer programming logic that tend to cause difficulties for beginners in addition to concepts that relate specifically to the MATLAB la...
journal_title:Science signaling
pub_type:
doi:10.1126/scisignal.2001984
更新日期:2011-09-13 00:00:00
abstract::New therapeutic approaches for chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis are needed because current treatments are often suboptimal in terms of both efficacy and the risks of serious adverse events. Inhibitor of apoptosis proteins (IAPs) are E3 ubiquitin liga...
journal_title:Science signaling
pub_type: 杂志文章,评审
doi:10.1126/scisignal.aax8295
更新日期:2020-02-18 00:00:00
abstract::Activation of Ca2+-sensitive, large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) by local, ryanodine receptor-mediated Ca2+ signals (Ca2+ sparks) acts as a brake on pressure-induced (myogenic) vasoconstriction-a fundamental mechanism that regulates blood flow in small resistance arteries...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aaf6625
更新日期:2016-10-11 00:00:00
abstract::Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis...
journal_title:Science signaling
pub_type: 杂志文章
doi:10.1126/scisignal.aaw5573
更新日期:2019-10-22 00:00:00