Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells

Under normal physiologic conditions, the glutathione S-transferase P1 (GSTP1) protein exists intracellularly as a dimer in reversible equilibrium with its monomeric subunits. In the latter form, GSTP1 binds to the mitogen-activated protein kinase, JNK, and inhibits JNK downstream signaling. In tumor cells, which frequently are characterized by constitutively high GSTP1 expression, GSTP1 undergoes phosphorylation by epidermal growth factor receptor (EGFR) at tyrosine residues 3, 7, and 198. Here we report on the effect of this EGFR-dependent GSTP1 tyrosine phosphorylation on the interaction of GSTP1 with JNK, on the regulation of JNK downstream signaling by GSTP1, and on tumor cell survival. Using in vitro and in vivo growing human brain tumors, we show that tyrosine phosphorylation shifts the GSTP1 dimer-monomer equilibrium to the monomeric state and facilitates the formation of the GSTP1-JNK complex, in which JNK is functionally inhibited. Targeted mutagenesis and functional analysis demonstrated that the increased GSTP1 binding to JNK results from phosphorylation of the GSTP1 C-terminal Tyr-198 by EGFR and is associated with a >2.5-fold decrease in JNK downstream signaling and a significant suppression of both spontaneous and drug-induced apoptosis in the tumor cells. The findings define a novel mechanism of regulatory control of JNK signaling that is mediated by the EGFR/GSTP1 cross-talk and provides a survival advantage for tumors with activated EGFR and high GSTP1 expression. The results lay the foundation for a novel strategy of dual EGFR/GSTP1 for treating EGFR+ve, GSTP1 expressing GBMs.     

Dust as a Nutrient Source for Fynbos Ecosystems,South Africa

Abstract Fynbos is the main vegetation of the Cape Floristic Region, a biodiversity hotspot that occurs in southwestern South Africa. A major question concerning the fynbos ecosystem is how it supports abundant and diverse vegetation on soils derived from nutrient-poor bedrock. In addition to marine aerosols (recycled sea salts), geochemical analyses reported here suggest that dust (aeolian) deposition represents a significant source of nutrients (for example, K, Ca and Zn) to the fynbos ecosystem. Headwater portions of the Boontjies River sub-catchment near the Cederberg Mountains support mountain fynbos communities that are entirely underlain by the Peninsula Formation, a quartz arenite with greater than 98 wt% SiO₂. Fynbos soils in these areas are composed of quartzose sand with 3–6 wt% kaolinitic clay and 1–2 wt% organic carbon. The minor amount of feldspar and mica minerals in the bedrock (0.5 wt% Al₂O₃) suggests an aeolian source for much of the clay minerals in the soil. The isotope composition of soluble Pb and Sr from fynbos vegetation and soils indicates a mixture of anthropogenic and terrigenous sources, most likely from washout of combusted petrol and dust from the arid interior particularly in association with Berg Wind events. Approximate mass balance calculations indicate that washout of aerosols provides an important source of nutrients such as Ca, K, P, Fe, Mn and Zn which the fynbos ecosystem is highly effective in retaining.     

Fas is expressed early in human thymocyte development but does not transmit an apoptotic signal.

We investigated the expression and function of Fas on human thymocytes prepared from fetal and pediatric tissue specimens and from SCID-hu Thy/Liv grafts. Unlike mouse thymocytes, human thymocytes exhibited a pattern of Fas expression skewed to immature cells, in that the highest expression was seen on double negative thymocytes and on intrathymic T progenitor cells. Fas expression was intermediate on double positive human thymocytes, and low or negative on mature single positive CD4 and CD8 medullary thymocytes. In spite of this relatively abundant surface expression, cross-linking of Fas with agonist mAb was incapable of triggering an apoptotic signal in human thymocytes. Apoptotic signaling was not enhanced by treatment with cycloheximide, nor by restoring a cosignaling milieu by addition of thymic stromal cells. Mouse thymocytes were induced to apoptosis by cross-linked recombinant soluble human Fas ligand both in vitro and in vivo, though human thymocytes were also resistant to this mode of receptor ligation. Membrane-bound Fas ligand also induced apoptotic death in murine thymocytes but not in human thymocytes. Human thymocytes were as sensitive as Jurkat cells, however, to apoptosis induced by TNF-alpha, suggesting that these cells have a signaling defect before activation of the earliest caspases. These data demonstrate a durable and specific resistance of human thymocytes to apoptosis induced through Fas receptor engagement, and reveal significant species-specific differences in the biology of thymocyte-programmed cell death.     

Substrate modification for enhanced native forest restoration,Reefton

Restoration of postmining substrates to native forest is a standard requirement of resource consents for mine sites located within areas of native forest in New Zealand. Unweathered waste rock presents significant challenges for plant growth, and past research highlights the importance of replacing soil as part of restoration. However, replacing soil with its horizon structure intact or even obtaining sufficient soil for restoration can be a challenge in some situations. In this paper, we describe the results of two trials undertaken at the OceanaGold Ltd. open‐cast gold mine in Reefton to explore the influence of substrate conditions on the growth of native forest seedlings. We show that beech (Nothofagus) seedlings grown on A‐horizon soil grew significantly better than those grown on soil mixed with waste rock, and both grew significantly better than plants grown just on waste rock. In the second trial, we show that bark chips are not a good substitute for soil. These results confirm the importance of having the correct substrate for successful native forest restoration.