FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK

Forkhead transcription factors of the FOXO class are negatively regulated by PKB/c-Akt in response to insulin/IGF signalling, and are involved in regulating cell cycle progression and cell death. Here we show that, in contrast to insulin signalling, low levels of oxidative stress generated by treatment with H 2 O 2 induce the activation of FOXO4. Upon treatment of cells with H 2 O 2 , the small GTPase Ral is activated and this results in a JNK-dependent phosphorylation of FOXO4 on threonine 447 and threonine 451. This Ral-mediated, JNK-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of FOXO4 after H 2 O 2 treatment. In addition, we show that this signalling pathway is also employed by tumor necrosis factor a to activate FOXO4 transcriptional activity. FOXO members have been implicated in cellular protection against oxidative stress via the transcriptional regulation of manganese superoxide dismutase and catalase gene expression. The results reported here, therefore, outline a homeostasis mechanism for sustaining cellular reactive oxygen species that is controlled by signalling pathways that can convey both negative (PI-3K/PKB) and positive (Ras/Ral) inputs

Evolution of the TOR Pathway

The TOR kinase is a major regulator of growth in eukaryotes. Many components of the TOR pathway are implicated in cancer and metabolic diseases in humans. Analysis of the evolution of TOR and its pathway may provide fundamental insight into the evolution of growth regulation in eukaryotes and provide a practical framework on which experimental evidence can be compared between species. Here we performed phylogenetic analyses on the components of the TOR pathway and determined their point of invention. We find that the two TOR complexes and a large part of the TOR pathway originated before the Last Eukaryotic Common Ancestor and form a core to which new inputs have been added during animal evolution. In addition, we provide insight into how duplications and sub-functionalization of the S6K, RSK, SGK and PKB kinases shaped the complexity of the TOR pathway. In yeast we identify novel AGC kinases that are orthologous to the S6 kinase. These results demonstrate how a vital signaling pathway can be both highly conserved and flexible in eukaryotes

Panta Rhei benchmark dataset: socio-hydrological data of paired events of floods and droughts

As the adverse impacts of hydrological extremes increase in many regions of the world, a better understanding of the drivers of changes in risk and impacts is essential for effective flood and drought risk management and climate adaptation. However, there is currently a lack of comprehensive, empirical data about the processes, interactions, and feedbacks in complex human–water systems leading to flood and drought impacts. Here we present a benchmark dataset containing socio-hydrological data of paired events, i.e. two floods or two droughts that occurred in the same area. The 45 paired events occurred in 42 different study areas and cover a wide range of socio-economic and hydro-climatic conditions. The dataset is unique in covering both floods and droughts, in the number of cases assessed and in the quantity of socio-hydrological data. The benchmark dataset comprises (1) detailed review-style reports about the events and key processes between the two events of a pair; (2) the key data table containing variables that assess the indicators which characterize management shortcomings, hazard, exposure, vulnerability, and impacts of all events; and (3) a table of the indicators of change that indicate the differences between the first and second event of a pair. The advantages of the dataset are that it enables comparative analyses across all the paired events based on the indicators of change and allows for detailed context- and location-specific assessments based on the extensive data and reports of the individual study areas. The dataset can be used by the scientific community for exploratory data analyses, e.g. focused on causal links between risk management; changes in hazard, exposure and vulnerability; and flood or drought impacts. The data can also be used for the development, calibration, and validation of sociohydrological models. The dataset is available to the public through the GFZ Data Services (Kreibich et al., 2023, https://doi.org/10.5880/GFZ.4.4.2023.001)

The challenge of unprecedented floods and droughts in risk management

Risk management has reduced vulnerability to floods and droughts globally1,2, yet their impacts are still increasing3. An improved understanding of the causes of changing impacts is therefore needed, but has been hampered by a lack of empirical data4,5. On the basis of a global dataset of 45 pairs of events that occurred within the same area, we show that risk management generally reduces the impacts of floods and droughts but faces difficulties in reducing the impacts of unprecedented events of a magnitude not previously experienced. If the second event was much more hazardous than the first, its impact was almost always higher. This is because management was not designed to deal with such extreme events: for example, they exceeded the design levels of levees and reservoirs. In two success stories, the impact of the second, more hazardous, event was lower, as a result of improved risk management governance and high investment in integrated management. The observed difficulty of managing unprecedented events is alarming, given that more extreme hydrological events are projected owing to climate change3

Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

The binding of insulin to its receptor initiates multiple signal transduction pathways regulating such diverse processes as proliferation, differentiation, glucose transport, and glycogen metabolism, The STAT-family of transcription factors has been demonstrated to play a critical role in gene induction by a variety of hemopoietic cytokines and hormones, Furthermore, constitutive activation of STATs is observed in transformed cells, Here we describe activation of a transcriptional complex binding to a consensus STAT-transcriptional element in response to insulin challenge, This complex is induced rapidly after tyrosine autophosphorylation of the insulin receptor, and is sustained for several hours, Supershift analysis of the insulin-induced complex reveals that it specifically contains the transcription factor Stat3, DAN binding of this complex is inhibited by pre-incubation with tyrosine, but not serine/threonine protein kinase inhibitors, whereas transcriptional activation is inhibited by both, Utilising a dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3 DNA-binding and also transactivation do not require p21ras, Furthermore, although previous studies have suggested a role for MAP kinases (ERKs) and PI-3K in STAT activation, utilising the specific MEK inhibitor PD098059 and the PI-3K inhibitor wortmannin, we demonstrate that activation of ERKs or PI-3K are not required for insulin induced Stat3 phosphorylation or transactivation

Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

The binding of insulin to its receptor initiates multiple signal transduction pathways regulating such diverse processes as proliferation, differentiation, glucose transport, and glycogen metabolism, The STAT-family of transcription factors has been demonstrated to play a critical role in gene induction by a variety of hemopoietic cytokines and hormones, Furthermore, constitutive activation of STATs is observed in transformed cells, Here we describe activation of a transcriptional complex binding to a consensus STAT-transcriptional element in response to insulin challenge, This complex is induced rapidly after tyrosine autophosphorylation of the insulin receptor, and is sustained for several hours, Supershift analysis of the insulin-induced complex reveals that it specifically contains the transcription factor Stat3, DAN binding of this complex is inhibited by pre-incubation with tyrosine, but not serine/threonine protein kinase inhibitors, whereas transcriptional activation is inhibited by both, Utilising a dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3 DNA-binding and also transactivation do not require p21ras, Furthermore, although previous studies have suggested a role for MAP kinases (ERKs) and PI-3K in STAT activation, utilising the specific MEK inhibitor PD098059 and the PI-3K inhibitor wortmannin, we demonstrate that activation of ERKs or PI-3K are not required for insulin induced Stat3 phosphorylation or transactivation

Shc associates with an unphosphorylated form of the p21ras guanine nucleotide exchange factor mSOS

Association of the p21ras guanine nucleotide exchange factor mSOS with tyrosine-phosphorylated Shc has been implicated in the activation of p21ras. In addition, after growth factor stimulation mSOS becomes phosphorylated as indicated by the appearance of a form of mSOS with reduced electrophoretic mobility. This phosphorylation is delayed with respect to Shc-Grb2-mSOS complex formation and activation of p21ras. To investigate the role of mSOS phosphorylation in further detail we have investigated the effect of phosphorylation on mSOS complex formation and p21ras activation. We found that Shc is associated with the unphosphorylated, faster migrating form of mSOS. Furthermore, although there is a correlation between the amount of complexes formed and the activation of p21ras, there is no such a correlation between mSOS phosphorylation and p21ras activation. In addition, inhibition of mSOS phosphorylation did not affect complex formation of mSOS with tyrosine phosphorylated Shc. Also, induction of mSOS phosphorylation prior to complex formation did not affect EGF-induced association of mSOS with Shc significantly, and Shc still associated predominantly with the faster migrating form of mSOS. From these results we conclude that the unphosphorylated form of mSOS is associated with Shc and that perhaps a phosphorylation-dephosphorylation step is part of the mSOS activation-inactivation cycl