[show abstract][hide abstract] ABSTRACT: Although stress can suppress growth and proliferation, cells can induce adaptive responses that allow them to maintain these functions under stress. While numerous studies have focused on the inhibitory effects of stress on cell growth, less is known on how growth-promoting pathways influence stress responses. We have approached this question by analyzing the effect of mammalian target of rapamycin (mTOR), a central growth controller, on the osmotic stress response. Our results showed that mammalian cells exposed to moderate hypertonicity maintained active mTOR, which was required to sustain their cell size and proliferative capacity. Moreover, mTOR regulated the induction of diverse osmostress response genes, including targets of the tonicity-responsive transcription factor NFAT5 as well as NFAT5-independent genes. Genes sensitive to mTOR-included regulators of stress responses, growth and proliferation. Among them, we identified REDD1 and REDD2, which had been previously characterized as mTOR inhibitors in other stress contexts. We observed that mTOR facilitated transcription-permissive conditions for several osmoresponsive genes by enhancing histone H4 acetylation and the recruitment of RNA polymerase II. Altogether, these results reveal a previously unappreciated role of mTOR in regulating transcriptional mechanisms that control gene expression during cellular stress responses.
Nucleic Acids Research 01/2012; 40(10):4368-84. · 8.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: We found that adenosine 5'-monophosphate-activated protein kinase (AMPK), which is considered the "fuel sensor" of mammalian cells because it directly responds to the depletion of the fuel molecule ATP, is strongly activated by tumor-like hypoxia and glucose deprivation. We also observed abundant AMPK activity in tumor cells in vivo, using subcutaneous tumor xenografts prepared from cells transformed with oncogenic H-Ras. Such rapidly growing transplants of tumor cells, however, represent fully developed tumors that naturally contain energetically stressed microenvironments that can activate AMPK. Therefore, to investigate the induction of AMPK activity during experimental tumorigenesis, we used an established model of brain tumor (glioma) development in the offspring of rats exposed prenatally to the mutagen N-ethyl-N-nitrosourea. We observed that immunostaining for a specific readout of AMPK activity (AMPK-dependent phosphorylation of acetyl-CoA carboxylase) was prominent during N-ethyl-N-nitrosourea-initiated neurocarcinogenesis, from the occurrence of early hyperplasia (microtumors) to the emergence of large gliomas. Moreover, we observed that immunostaining for activating phosphorylation of AMPK correlated with the same stages of glioma development, notably in mitotic tumor cells in which the signal showed punctate as well as cytoplasmic patterns associated with spindle formation. Based on these observations, we propose that neurocarcinogenesis requires AMPK-dependent regulation of cellular energy metabolism.
International Journal of Cancer 05/2011; 128(9):2230-9. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Angiogenesis is one of the major processes controlling growth and metastasis of tumors. Angiogenesis inhibitors have been targeted for the treatment of various cancers for more than 2 decades. We have developed a novel class of steroidal compounds aimed at blocking the angiogenic process in cancerous tissues. Our lead compound, SR16388, is a potent antiangiogenic agent with binding affinity to estrogen receptor-α (ER-α) and -β (ER-β) at the nanomolar range. This compound inhibited the proliferation of human microvascular endothelial cells (HMVEC) and various types of human cancer cells in vitro. SR16388 inhibited embryonic angiogenesis as measured in the chick chorioallantoic membrane (CAM) assay. The blood vessel density in the CAM was greatly reduced after the embryos were treated with 3 μg/CAM of SR16388 for 24 h. SR16388 at a dose of 2 μM prevented tube formation in Matrigel after HMVEC cells were treated for 8 h. In a modified Boyden chamber assay, SR16388 inhibited the migration of HMVECs by 80% at 500 nM. Using a novel in vivo Fibrin Z-chamber model, we demonstrated that SR16388 at a single daily oral dose of 3 mg/kg for 12 days significantly inhibited the granulation tissue (GT) thickness and the microvessel density of the GT as compared to control. More importantly, SR16388 down-regulated the pro-angiogenic transcription factors, hypoxia inducible factor 1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) in non-small cell lung cancer (NSCLC) cells. Together, these effects of SR16388 can lead to the reduction of vascularization and tumor growth in vivo.
[show abstract][hide abstract] ABSTRACT: The orphan nuclear receptor estrogen-related receptor alpha (ERRalpha) has been implicated in the development of various human malignancies, including breast, prostate, ovary, and colon cancer. ERRalpha, bound to a co-activator protein (e.g., peroxisome proliferator receptor gamma co-activator-1alpha, PGC-1alpha), regulates cellular energy metabolism by activating transcription of genes involved in various metabolic processes, such as mitochondrial genesis, oxidative phosphorylation, and fatty acid oxidation. Accumulating evidence suggests that ERRalpha is a novel target for solid tumor therapy, conceivably through effects on the regulation of tumor cell energy metabolism associated with energy stress within solid tumor microenvironments. This report describes a novel steroidal antiestrogen (SR16388) that binds selectively to ERRalpha, but not to ERRbeta or ERRgamma, as determined using a time-resolved fluorescence resonance energy transfer assay. SR16388 potently inhibits ERRalpha's transcriptional activity in reporter gene assays, and prevents endogenous PGC-1alpha and ERRalpha from being recruited to the promoters or enhancers of target genes. Representative in vivo results show that SR16388 inhibited the growth of human prostate tumor xenografts in nude mice as a single agent at 30mg/kg given once daily and 100mg/kg given once weekly. In a combination study, SR16388 (10mg/kg, once daily) and paclitaxel (7.5mg/kg, twice weekly) inhibited the growth of prostate tumor xenografts in nude mice by 61% compared to untreated xenograft tumors. SR16388 also inhibited the proliferation of diverse human tumor cell lines after a 24-h exposure to the compound. SR16388 thus has utility both as an experimental antitumor agent and as a chemical probe of ERRalpha biology.
[show abstract][hide abstract] ABSTRACT: We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK.
[show abstract][hide abstract] ABSTRACT: AMPK has been termed the fuel sensor of mammalian cells because it directly responds to the depletion of the fuel molecule ATP. In previous work, we found that AMPK is strongly activated by tumor-like hypoxia and glucose deprivation, independently of the oxygen response system associated with HIF-1. We also observed high levels of AMPK activity in tumor cells in vivo, using different model tumors. These findings suggested the hypothesis that modulation of AMPK activity could have therapeutic value for the treatment of solid tumors. To investigate this hypothesis, we have been conducting a SAR study of potential small-molecule modulators of AMPK activity. Here we report that the chemotherapeutic drug SU11248 (sunitinib) is at least as potent an inhibitor of AMPK as compound C, which is a commonly used experimental direct inhibitor of the enzyme. We also provide a computational model of the binding pose of SU11248 to an AMPKα subunit, which suggests a structural basis for the affinity of the drug for the ATP site of the catalytic domain. The ability of SU11248 to inhibit AMPK has potential clinical significance--there may be populations of SU11248-treated patients in which AMPK activity is inhibited in normal as well as in tumor tissue.
Cancer biology & therapy 07/2010; 10(1):68-76. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: We previously identified metal-responsive transcription factor-1 (MTF-1) as a positive contributor to mouse fibrosarcoma growth through effects on cell survival, proliferation, tumor angiogenesis and extracellular matrix remodeling. In the present study, we investigated MTF-1 protein expression in human tissues by specific immunostaining of both normal and tumor tissue samples. Immunohistochemical (IHC) staining of a human tissue microarray (TMA), using a unique anti-human MTF-1 antibody, indicated constitutive MTF-1 expression in most normal tissues, with liver and testis displaying comparatively high levels of expression. Nevertheless, MTF-1 protein levels were found to be significantly elevated in diverse human tumor types, including breast, lung and cervical carcinomas. IHC analysis of a separate panel of full-size tissue sections of human breast cancers, including tumor and normal adjacent, surrounding tissue, confirmed and extended the results of the TMA analysis. Taken with our previous findings, this new study suggests a role for MTF-1 in human tumor development, growth or spread. Moreover, the study suggests that MTF-1 could be a novel therapeutic target that offers the opportunity to manipulate metal or redox homeostasis in tumor cells.
Cancer biology & therapy 03/2010; 9(6):469-76. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: The peroxisome proliferator-activated receptor delta (PPARdelta) is a ligand-activated, nuclear receptor transcription factor that has a documented role in glucose and lipid homeostasis. Recent studies have implicated this nuclear receptor in numerous aspects of oncogenesis. We report herein the characterization of a novel small-molecule (SR13904) that inhibits PPARdelta agonist-induced transactivation and functions as a PPARdelta antagonist. SR13904 also antagonizes PPARgamma transactivation, albeit with much weaker potency. SR13904 displays inhibitory effects on cellular proliferation and survival in several human carcinoma lines, including lung, breast and liver. These inhibitory effects of SR13904 on tumor cells were linked to a G(1)/S cell cycle block and increased apoptosis. Molecular studies show that SR13904 treatment of a lung cancer cell line, A549, results in markedly reduced levels of a number of cell cycle proteins including cyclin A and D, and cyclin dependent kinase (CDK) 2 and 4. The inhibitory effects on CDK2 appear to be transcriptional. Several of these cell cycle-related genes are known to be upregulated by PPARdelta. The antitumor activities of SR13904 suggest that antagonism of PPARdelta-mediated transactivation may inhibit tumorigenesis and that pharmacological inhibition of PPARdelta may be a potential strategy for treatment or prevention of cancer.
Cancer biology & therapy 08/2009; 8(13):1252-61. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EgfR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes.
We were interested in identifying subnetworks within the EgfR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EgfR-MAPK signaling. This model was composed of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype-specific subnetworks, including one that suggested Pak1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that Pak1 over-expressing cell lines would have increased sensitivity to Mek inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three Mek inhibitors. We found that Pak1 over-expressing luminal breast cancer cell lines are significantly more sensitive to Mek inhibition compared to those that express Pak1 at low levels. This indicates that Pak1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to Mek inhibitors.
All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.
[show abstract][hide abstract] ABSTRACT: In wound healing, myofibroblast transdifferentiation (MFT) is a metaplastic change in phenotype producing profibrotic effector cells that secrete and remodel the extracellular matrix. Unlike pathways that induce MFT, the molecular mechanisms that negatively regulate MFT are poorly understood. Here, we report that AMP-activated protein kinase (AMPK) blocks MFT in response to transforming growth factor-beta (TGFbeta). Pharmacological activation of AMPK inhibited TGFbeta-induced secretion of extracellular matrix proteins collagen types I and IV and fibronectin. AMPK activation also prevented induction of the myofibroblast phenotype markers alpha-smooth muscle actin and the ED-A fibronectin splice variant. AMPK activators did not prevent MFT in cells transduced with an adenovirus expressing dominant negative, kinase-dead AMPKalpha2. Moreover, AMPK activators did not inhibit MFT induction in AMPK(alpha1,2)(-/-) fibroblasts, demonstrating a requirement for AMPK(alpha) expression. Adenoviral transduction of constitutively active AMPK(alpha2) was sufficient to prevent TGFbeta-induced collagen I, alpha-smooth muscle actin, and ED-A fibronectin. AMPK did not reduce TGFbeta-stimulated Smad3 COOH-terminal phosphorylation and nuclear translocation, which are necessary for MFT. However, AMPK activation inhibited TGFbeta-induced transcription driven by Smad3-binding cis-elements. Consistent with a role for AMPK in transcriptional regulation, nuclear translocation of AMPKalpha2 correlated with the appearance of active AMPKalpha in the nucleus. Collectively, these results demonstrate that AMPK inhibits TGFbeta-induced transcription downstream of Smad3 COOH-terminal phosphorylation and nuclear translocation. Furthermore, activation of AMPK is sufficient to negatively regulate MFT in vitro.
Journal of Biological Chemistry 05/2008; 283(16):10461-9. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: A network of reactions is a commonly used paradigm for rep- resenting knowledge about a biological process. How does one understand such generic networks and answer queries using them? In this paper, we present a novel approach based on translation of generic reaction net- works to Boolean weighted MaxSAT. The Boolean weighted MaxSAT instance is generated by encoding the equilibrium configurations of a re- action network by weighted boolean clauses. The important feature of this translation is that it uses reactions, rather than the species, as the boolean variables. Existing weighted MaxSAT solvers are used to solve the generated instances and find equilibrium configurations. This method of analyzing reaction networks is generic, flexible and scales to large mod- els of reaction networks. We present a few case studies to validate our claims.
Algebraic Biology, Second International Conference, AB 2007, Castle of Hagenberg, Austria, July 2-4, 2007, Proceedings; 01/2007
[show abstract][hide abstract] ABSTRACT: Many dynamical processes can be represented as directed attributed graphs or Petri nets where relationships between various entities are explicitly expressed. Signaling networks modeled as Petri nets are one class of such graphical modeling and representations. These networks encode how different protein in specific compartments, interact to create new protein products. Initially, the proteins and rules governing their interactions are curated from literature and then refined with experimental data. Variation in these networks occurs in topological structure, size, and weights associated on edges. Collectively, these variations are quite significant for manual and interactive analysis. Furthermore, as new information is added to these networks, the emergence of new computational models becomes paramount. From this perspective, hierarchical spectral methods are proposed and applied for inferring similarities and dissimilarities from an ensemble of graphs that corresponds to reaction networks. The technique has been implemented and tested on curated signaling networks that are derived for breast cancer cell lines
Proceedings of the 2007 IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology, CIBCB 2007, Honolulu, Hawaii, USA, April 1-5, 2007, Part of the IEEE Symposium Series on Computational Intelligence (IEEE SSCI 2007); 01/2007
[show abstract][hide abstract] ABSTRACT: Low oxygen gradients (hypoxia and anoxia) are important determinants of pathological conditions under which the tissue blood supply is deficient or defective, such as in solid tumors. We have been investigating the relationship between the activation of hypoxia-inducible factor 1 (HIF-1), the primary transcriptional regulator of the mammalian response to hypoxia, and 5'-AMP-activated protein kinase (AMPK), another regulatory system important for controlling cellular energy metabolism. In the present study, we used mouse embryo fibroblasts nullizygous for HIF-1alpha or AMPK expression to show that AMPK is rapidly activated in vitro by both physiological and pathophysiological low-oxygen conditions, independently of HIF-1 activity. These findings imply that HIF-1 and AMPK are components of a concerted cellular response to maintain energy homeostasis in low-oxygen or ischemic-tissue microenvironments. Finally, we used transformed derivatives of wild-type and HIF-1alpha- or AMPKalpha-null mouse embryo fibroblasts to determine whether AMPK is activated in vivo. We obtained evidence that AMPK is activated in authentic hypoxic tumor microenvironments and that this activity overlaps with regions of hypoxia detected by a chemical probe. We also showed that AMPK is important for the growth of this tumor model.
Molecular and Cellular Biology 08/2006; 26(14):5336-47. · 5.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypoxia-inducible factor-1 (HIF-1), the major transcriptional regulator of the mammalian cellular response to low oxygen (hypoxia), is embedded within a complex network of signaling pathways. We have been investigating the importance of another stress-responsive transcription factor, MTF-1, for the adaptation of cells to hypoxia. This article reports that MTF-1 plays a central role in hypoxic cells by contributing to HIF-1 activity. Loss of MTF-1 in transformed Mtf1 null mouse embryonic fibroblasts (MEFs) results in an attenuation of nuclear HIF-1alpha protein accumulation, HIF-1 transcriptional activity, and expression of an established HIF-1 target gene, glucose transporter-1 (Glut1). Mtf1 null (Mtf1 KO) MEFs also have constitutively higher levels of both glutathione (GSH) and the rate-limiting enzyme involved in GSH synthesis--glutamate cysteine ligase catalytic subunit--than wild type cells. The altered cellular redox state arising from increased GSH may perturb oxygen-sensing mechanisms in hypoxic Mtf1 KO cells and decrease the accumulation of HIF-1alpha protein. Together, these novel findings define a role for MTF-1 in the regulation of HIF-1 activity.
Biochemical and Biophysical Research Communications 12/2005; 337(3):860-7. · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: The Pathalyzer is a program for analyzing large-scale signal trans- duction networks. Reactions and their substrates and products are represented as transitions and places in a safe Petri net. The user can interactively specify goal states, such as activation of a particular protein in a particular cell site, and the system will automatically find and display a pathway that results in the goal state - if possible. The user can also require that the pathway be generated without using certian proteins. The system can also find all individual places and all pairs of places which, if knocked out, would prevent the goals from being achieved. The tool is intended to be used by biologists with no significant understanding of Petri nets or any of the other concepts used in the implementation.
Systems Biology and Regulatory Genomics, Joint Annual RECOMB 2005 Satellite Workshops on Systems Biology and on Regulatory Genomics, San Diego, CA, USA; December 2-4, 2005, Revised Selected Papers; 01/2005
[show abstract][hide abstract] ABSTRACT: Hypoxia-inducible factor-1 (HIF-1) is a critical regulator of the transcriptional response to low oxygen conditions (hypoxia/anoxia) experienced by mammalian cells in both physiological and pathophysiological circumstances. As our understanding of the biology and biochemistry of HIF-1 has grown, it has become apparent that cells adapt to signals generated by low oxygen through a network of stress responsive transcription factors or complexes, which are influenced by HIF-1 activity. This review summarizes our current understanding of the interaction of HIF-1 with AP-1, a classic example of a family of pleiotropic transcription factors that impact on diverse cellular processes and phenotypes, including the adaptation to low oxygen stress. The review focuses on experimental studies involving cultured cells exposed to hypoxia/anoxia, and describes both established and possible interactions between HIF-1 and AP-1 at different levels of cellular organization.
Seminars in Cell and Developmental Biology 01/2005; 16(4-5):502-13. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypoxia and anoxia are important microenvironmental stresses that contribute to pathological events such as solid-tumor development. We have been investigating the effects of hypoxia and anoxia on expression of the proto-oncogene c-jun and the regulation of c-Jun/AP-1 transcription factors. In earlier work using genetically manipulated mouse embryo fibroblasts (mEFs), we found a functional relationship among c-jun expression, c-Jun N-terminal phosphorylation, and the presence of hypoxia-inducible factor 1 alpha (HIF-1 alpha), the oxygen-regulated subunit of the HIF-1 transcription factor. Both the induction of c-jun mRNA expression and c-Jun N-terminal phosphorylation in cells exposed to hypoxia or anoxia were found to be dependent on the presence of HIF-1 alpha, but this was not the case in cells exposed to less-severe hypoxia. Here we describe new findings concerning HIF-1-dependent c-Jun N-terminal phosphorylation in cells exposed to hypoxia or anoxia. Specifically, we report that hypoxia-inducible c-Jun N-terminal kinase (JNK) activity, which involves JNKs or stress-activated protein kinases (SAPKs), is dependent on enhanced glucose utilization mediated by HIF-1. These results suggest a model in which hypoxia-inducible JNK activity is connected to oxygen sensing through increased glucose absorption and/or glycolytic activity regulated by the HIF-1 system. We also found that basal threonine and tyrosine phosphorylation (within the TEY motif) of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the corresponding ERK1/2 activity were defective in hypoxic HIF-1 alpha-null mEFs but not in wild-type mEFs, independently of glucose uptake. Therefore, the activities of both JNKs/SAPKs and ERK1/2 are sensitive to HIF-1-dependent processes in cells exposed to hypoxia or anoxia.
Molecular and Cellular Biology 06/2004; 24(10):4128-37. · 5.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypoxia and anoxia are important microenvironmental stresses that contribute to pathological events such as solid-tumor development. We have been investigating the effects of hypoxia and anoxia on expression of the proto-oncogene c-jun and the regulation of c-Jun/AP-1 transcription factors. In earlier work using genetically manipulated mouse embryo fibroblasts (mEFs), we found a functional relationship among c-jun expression, c-Jun N-terminal phosphorylation, and the presence of hypoxia-inducible factor 1 (HIF-1), the oxygen- regulated subunit of the HIF-1 transcription factor. Both the induction of c-jun mRNA expression and c-Jun N-terminal phosphorylation in cells exposed to hypoxia or anoxia were found to be dependent on the presence of HIF-1, but this was not the case in cells exposed to less-severe hypoxia. Here we describe new findings concerning HIF-1-dependent c-Jun N-terminal phosphorylation in cells exposed to hypoxia or anoxia. Specif- ically, we report that hypoxia-inducible c-Jun N-terminal kinase (JNK) activity, which involves JNKs or stress-activated protein kinases (SAPKs), is dependent on enhanced glucose utilization mediated by HIF-1. These results suggest a model in which hypoxia-inducible JNK activity is connected to oxygen sensing through increased glucose absorption and/or glycolytic activity regulated by the HIF-1 system. We also found that basal threonine and tyrosine phosphorylation (within the TEY motif) of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the corresponding ERK1/2 activity were defective in hypoxic HIF-1-null mEFs but not in wild-type mEFs, independently of glucose uptake. Therefore, the activities of both JNKs/SAPKs and ERK1/2 are sensitive to HIF-1-dependent processes in cells exposed to hypoxia or anoxia. The c-Jun protein is a subunit of AP-1 transcription factors, pleiotropic regulators that influence the proliferation, survival, and differentiation of both normal and transformed cells (re- viewed in references 34, 52, and 63). We have been investigat- ing the response of c-Jun/AP-1 to low-oxygen conditions (hyp- oxia and anoxia), particularly those present within the microenvironments of solid tumors (3, 27-29). The transcrip- tional and posttranscriptional activation of c-Jun/AP-1 by hy- poxic or anoxic stress has been reported for various normal and transformed cells (2, 3, 5, 36, 45, 60, 64, 65), indicating that it is generally sensitive to changes in ambient oxygen concentra- tion. Recently we demonstrated that phosphorylation of c-Jun within its N-terminal region in cells exposed to hypoxia or anoxia is dependent on the presence of hypoxia-inducible fac- tor 1 (HIF-1) (27), the principal transcriptional regulator of hypoxia-responsive gene expression in mammalian cells (re- cently reviewed in references 19, 51, and 61). In general, we found that the pattern of hypoxia-inducible c-Jun N-terminal phosphorylation is biphasic, consisting of early HIF-1-indepen- dent and late HIF-1-dependent components (27). The func- tional relationship demonstrated between c-Jun/AP-1 and HIF-1 in hypoxic cells (2, 27) suggests a high level of organi- zation—a network ensuring that hypoxic or anoxic signals are interpreted appropriately in a particular cell or tissue. Little is known, however, of the pathways responsible for the activation of c-Jun/AP-1 by hypoxic signals.
Molecular and Cellular Biology - MOL CELL BIOL. 01/2004; 24(10):4128-4137.
[show abstract][hide abstract] ABSTRACT: In this paper we describe the use of the rewriting logic based Maude tool to model and analyze mammalian signaling pathways. We discuss the representation of the underlying biological concepts and events and describe the use of the new search and model checking capabilities of Maude 2.0 to analyze the modeled network. We also discuss the use of Maude's reflective capability for meta modeling and analyzing the models themselves. The idea of symbolic biological experiments opens up an exciting new world of challenging applications for formal methods in general and for rewriting logic based formalisms in particular.
Electronic Notes in Theoretical Computer Science. 07/2003;
[show abstract][hide abstract] ABSTRACT: We describe the application of Maude, a symbolic language founded on rewriting logic, to the modeling of functional domains
within signaling proteins, within the framework of the Pathway Logic project. Protein functional domains (PFDs) are a critical
focus of modern signal transduction research. Recently, it has become apparent that signaling proteins must behave combinatorially
to generate the high levels of complexity and versatility observed in signaling networks, and that PFDs are responsible for
at least part of this capability. In our approach, the state of a system consisting of proteins and PFDs is represented as
a term in an equational theory and rewrite rules.
Computational Methods in Systems Biology, First International Workshop, CMSB 2003, Roverto, Italy, February 24-26, 2003, Proceedings; 01/2003