SPIKE – a database, visualization and analysis tool of cellular signaling pathways

Elkon, Ran; Vesterman, Rita; Amit, Nira; Ulitsky, Igor; Zohar, Idan; Weisz, Mali; Mass, Gilad; Orlev, Nir; Sternberg, G; Blekhman, Ran; Assa, Jackie; Shiloh, Yosef; Shamir, Ron

doi:10.1186/1471-2105-9-110

Cited by 54 publications

(35 citation statements)

References 29 publications

(29 reference statements)

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“…Mass Spectrometry-The TiO 2 column eluates were dried using a SpeedVac and C 18 Stage tip-purified (12). MS analysis was performed on an LTQ-Orbitrap (13) (Thermo Fisher Scientific) connected to an Agilent 1200 nanoflow HPLC system (Agilent) using a nanoelectrospray ion source (Proxeon Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Site-specific Phosphorylation Dynamics of the Nuclear Proteome during the DNA Damage Response

Bennetzen

Larsen

Bunkenborg

et al. 2010

Molecular & Cellular Proteomics

228

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To investigate the temporal regulation of the DNA damage response, we applied quantitative mass spectrometrybased proteomics to measure site-specific phosphorylation changes of nuclear proteins after ionizing radiation. We profiled 5204 phosphorylation sites at five time points following DNA damage of which 594 sites on 209 proteins were observed to be regulated more than 2-fold. Of the 594 sites, 372 are novel phosphorylation sites primarily of nuclear origin. The 594 sites could be classified to distinct temporal profiles. Sites regulated shortly after radiation were enriched in the ataxia telangiectasia mutated (ATM) kinase SQ consensus sequence motif and a novel SXXQ motif. Importantly, in addition to induced phosphorylation, we identified a considerable group of sites that undergo DNA damage-induced dephosphorylation. Together, our data extend the number of known phosphorylation sites regulated by DNA damage, provides so far unprecedented temporal dissection of DNA damage-modified phosphorylation events, and elucidate the cross-talk between different types of post-translational modifications in the dynamic regulation of a multifaceted DNA damage response.

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Section: Methodsmentioning

confidence: 99%

Site-specific Phosphorylation Dynamics of the Nuclear Proteome during the DNA Damage Response

Bennetzen

Larsen

Bunkenborg

et al. 2010

Molecular & Cellular Proteomics

228

View full text Add to dashboard Cite

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“…The choice of protein-protein interaction instead of gene coexpression networks (used in Ref. 33) is not essential to NSEA; however, it is believed that protein-protein interactions more reliably reflect underlying biology by capturing signaling, binding, and other biochemical interactions between molecules. The use of IPA for biological network analysis could similarly be replaced with any other proprietary or public network database (e.g.…”

Section: Discussionmentioning

confidence: 99%

Integrated Proteomic, Transcriptomic, and Biological Network Analysis of Breast Carcinoma Reveals Molecular Features of Tumorigenesis and Clinical Relapse

Imieliński

Cha

Rejtar

et al. 2012

Molecular & Cellular Proteomics

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“…With limited experimental data available, our model was constructed based on established biological facts and reasonable simplifications. We also plotted schematic diagrams to depict cross-talk between the p53 and E2F1 pathways (23). The key points of the model are addressed as follows.…”

Section: Methodsmentioning

confidence: 99%

Coordination between Cell Cycle Progression and Cell Fate Decision by the p53 and E2F1 Pathways in Response to DNA Damage

Zhang

Liu

Wang

2010

Journal of Biological Chemistry

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After DNA damage, cells must decide between different fates including growth arrest, DNA repair, and apoptosis. Both p53 and E2F1 are transcription factors involved in the decision process. However, the mechanism for cross-talk between the p53 and E2F1 pathways still remains unclear. Here, we proposed a four-module kinetic model of the decision process and explored the interplay between these two pathways in response to ionizing radiation via computer simulation. In our model the levels of p53 and E2F1 separately exhibit pulsatile and switching behaviors. Upon DNA damage, p53 is first activated, whereas E2F1 is inactivated, leading to cell cycle arrest in the G 1 phase. We found that the ultimate decision between cell life and death is determined by the number of p53 pulses depending on the extent of DNA damage. For repairable DNA damage, the cell can survive and reenter the S phase because of the activation of E2F1 and inactivation of p53. For irreparable DNA damage, growth arrest is overcome by growth factors, and activated p53 and E2F1 cooperate to initiate apoptosis. We showed that E2F1 promotes apoptosis by up-regulating the proapoptotic cofactors of p53 and procaspases. It was also revealed that deregulated E2F1 by oncogene activation can make cells sensitive to DNA damage even in low serum medium. Our model consistently recapitulates the experimental observations of the intricate relationship between p53 and E2F1 in the DNA damage response. This work underscores the significance of E2F1 in p53-mediated cell fate decision and may provide clues to cancer therapy.The tumor suppressor p53 has a crucial role in preventing tumorigenesis (1). Upon various stresses, p53 is stabilized and activated to function primarily as a transcription factor, regulating the expression of a large number of genes involved in cell cycle arrest, DNA repair, or apoptosis (2). Thus, p53 is at the hub of numerous signaling pathways triggered by various stresses. Previously, it was proposed that cell fate after DNA damage is governed by p53 levels, i.e. a low level of p53 leads to transient growth arrest and cell survival, whereas a high level promotes irreversible apoptosis (3). Recently, it has been reported that p53 levels can exhibit oscillations in response to DNA damage induced by ionizing radiation (IR) (4, 5). Whereas damped oscillations of p53 levels were observed at the population level (4), a series of undamped pulses was observed at the single-cell level (5). In such a digital mode, it is the number of p53 pulses rather than their amplitudes and duration that is related to the extent of DNA damage and determines cell fate (5). p53 pulses can be generated by negative feedback loops with time delay (6 -8) or coupled positive and negative feedback loops (9, 10).How stressed cells exploit p53 pulses to translate various stresses into different cellular outcomes is not completely understood. Several studies have explored the functional roles of p53 pulses in response to DNA damage. Tyson and co-workers (10) classified active p5...

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SPIKE – a database, visualization and analysis tool of cellular signaling pathways

Cited by 54 publications

References 29 publications

Site-specific Phosphorylation Dynamics of the Nuclear Proteome during the DNA Damage Response

Site-specific Phosphorylation Dynamics of the Nuclear Proteome during the DNA Damage Response

Integrated Proteomic, Transcriptomic, and Biological Network Analysis of Breast Carcinoma Reveals Molecular Features of Tumorigenesis and Clinical Relapse

Coordination between Cell Cycle Progression and Cell Fate Decision by the p53 and E2F1 Pathways in Response to DNA Damage

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