A central role for p38 MAPK in the early transcriptional response to stress

Abstract The mitogen-activated protein kinase p38 (p38 MAPK) is activated by a number of stresses. A recent study in BMC Genomics has uncovered the early transcriptional responses to three types of stress and has demonstrated a central role for p38 MAPK in mediating these responses. See research article http://www.biomedcentral.com/1471-2164/11/144</p

Cancer: A new role for an old enemy

Drugs that change the shape of AKT, a protein kinase that promotes tumor growth, may be more effective than drugs that only target its enzymatic activity

Discovery of a gatekeeper residue in the C terminal tail of the extracellular signal-regulated protein kinase 5 (ERK5)

The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C terminal transactivation domain of ERK5. We have found that Thr732 acted as a functional gatekeeper residue controlling C terminal-mediated nuclear translocation and transcriptional enhancement. Consistently, using a non-bias quantitative mass spectrometry approach, we demonstrated that phosphorylation at Thr732 conferred selectivity for binding interactions of ERK5 with proteins related to chromatin and RNA biology, whereas a number of metabolic regulators were associated with full-length wild type ERK5. Additionally, our proteomic analysis revealed that phosphorylation of the Ser730-Glu-Thr732-Pro motif could occur independently of dual phosphorylation at Thr218-Glu-Tyr220 in the activation loop. Together these results firmly establish the significance of C terminal phosphorylation in regulating ERK5 function, independently of MEK5. This novel mechanism may be of particular relevance in cancer cells where ERK5 has be found to be hyperphosphoryated on its C terminal tail

Regulation of c-Jun NH2-terminal Kinase ( Jnk) Gene Expression during T Cell Activation

The c-Jun NH2-terminal kinases (JNKs) are a group of mitogen-activated protein (MAP) kinases that participate in signal transduction events mediating specific cellular functions. Activation of JNK is regulated by phosphorylation in response to cellular stress and inflammatory cytokines. Here, we demonstrate that JNK is regulated by a second, novel mechanism. Induction of Jnk gene expression is required in specific tissues before activation of this signaling pathway. The in vivo and in vitro ligation of the T cell receptor (TCR) leads to induction of JNK gene and protein expression. TCR signals are sufficient to induce JNK expression, whereas JNK phosphorylation also requires CD28-mediated costimulatory signals. Therefore, both expression and activation contribute to the regulation of the JNK pathway to ensure proper control during the course of an immune response

Understanding risks and resilience of private boreholes in Lagos, Nigeria

Water security is one of the most pressing risks facing the world. In urban areas, rapidly growing population coupled with rising incomes, falling costs, and often an absent or unreliable public water supply, mean that increasing numbers of households are choosing to install private boreholes to meet their domestic water needs. This trend is particularly prevalent in emerging global mega-cities such as Lagos, Nigeria. Through a series of internet, household, and water point surveys, this multidisciplinary study begins to address the question: does the proliferation of private boreholes strengthen or weaken the resilience of Lagos and its residents to future environmental shocks? A broad internet survey shows that 68% of 500 respondents make use of private boreholes on a daily basis, either as their primary water source or used conjunctively with other sources. Attitudes to groundwater are overwhelmingly positive, with a majority considering this a reliable source in terms of quality and quantity, and agreeing that access to a private borehole increases households’ water security, helping families to cope with possible water shortages in future. The majority of borehole owners perceive no risks associated with long-term groundwater availability, with 89% agreeing that water is abundant and 86% holding the view that borehole owners should be able to abstract as much water as they like. The results of a focused water-point and household survey, carried out at 40 private groundwater sources across Lagos, agree with these findings. Of those surveyed, the majority derive their domestic water from privately owned hand-dug wells and boreholes, and sachet water. Water point users have positive perceptions of the water quality from these sources, with 90% of boreholes and 80% of hand-dug wells thought to provide good quality water. However, water quality analyses show that individual’s perceptions do not always reflect reality. One third of boreholes and over 80% of shallow wells surveyed display unsafe levels of E. Coli. Of those sources perceived as good quality, almost 40% are classed as unsafe for drinking, according to measured levels of E. Coli. The collective enthusiasm for unlimited and expanding groundwater extraction in the city of Lagos coupled with a demonstrated lack of groundwater governance and regulation, while increasing individuals’ resilience to issues of water shortage in the present, may decrease the resilience of the wider community in the long-term. Understanding the role of agency and communicating the potential risks associated with uncontrolled groundwater development, across a range of actors and agencies, may be critical to avoid future conflict between individual and societal resilience to environmental shocks

The JNK Pathway Regulates the In Vivo Deletion of Immature CD4+CD8+ Thymocytes

The extracellular signal-regulated kinase (ERK), the c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase pathways are triggered upon ligation of the antigen-specific T cell receptor (TCR). During the development of T cells in the thymus, the ERK pathway is required for differentiation of CD4−CD8− into CD4+CD8+ double positive (DP) thymocytes, positive selection of DP cells, and their maturation into CD4+ cells. However, the ERK pathway is not required for negative selection. Here, we show that JNK is activated in DP thymocytes in vivo in response to signals that initiate negative selection. The activation of JNK in these cells appears to be mediated by the MAP kinase kinase MKK7 since high levels of MKK7 and low levels of Sek-1/MKK4 gene expression were detected in thymocytes. Using dominant negative JNK transgenic mice, we show that inhibition of the JNK pathway reduces the in vivo deletion of DP thymocytes. In addition, the increased resistance of DP thymocytes to cell death in these mice produces an accelerated reconstitution of normal thymic populations upon in vivo DP elimination. Together, these data indicate that the JNK pathway contributes to the deletion of DP thymocytes by apoptosis in response to TCR-derived and other thymic environment– mediated signals

A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei through retrograde signalling pathways that modulate nuclear gene expression to maintain mitochondrial homeostasis. The monooxygenase CLK-1 (human homologue COQ7) was previously reported to be mitochondrial, with a role in respiration and longevity. We have uncovered a distinct nuclear form of CLK-1 that independently regulates lifespan. Nuclear CLK-1 mediates a retrograde signalling pathway that is conserved from Caenorhabditis elegans to humans and is responsive to mitochondrial reactive oxygen species, thus acting as a barometer of oxidative metabolism. We show that, through modulation of gene expression, the pathway regulates both mitochondrial reactive oxygen species metabolism and the mitochondrial unfolded protein response. Our results demonstrate that a respiratory enzyme acts in the nucleus to control mitochondrial stress responses and longevity