Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells

BACKGROUND: Glucocorticoids are frequently used as a primary chemotherapeutic agent in many types of human lymphoid malignancies because they induce apoptosis through activation of the glucocorticoid receptor, with subsequent alteration of a complex network of cellular mechanisms. Despite clinical usage for over fifty years, the complete mechanism responsible for glucocorticoid-related apoptosis or resistance remains elusive. The mitogen-activated protein kinase pathway is a signal transduction network that influences a variety of cellular responses through phosphorylation of specific target substrates, including the glucocorticoid receptor. In this study we have evaluated the pharmaceutical scenarios which converge on the mitogen-activated protein kinase pathway to alter glucocorticoid sensitivity in clones of human acute lymphoblastic CEM cells sensitive and refractory to apoptosis in response to the synthetic glucocorticoid dexamethasone. RESULTS: The glucocorticoid-resistant clone CEM-C1-15 displays a combination of high constitutive JNK activity and dexamethasone-induced ERK activity with a weak induction of p38 upon glucocorticoid treatment. The cells become sensitive to glucocorticoid-evoked apoptosis after: (1) inhibition of JNK and ERK activity, (2) stimulation of the cAMP/PKA pathway with forskolin, or (3) inhibition of mTOR with rapamycin. Treatments 1–3 in combination with dexamethasone alter the intracellular balance of phospho-MAPKs by lowering JNK phosphorylation and increasing the level of glucocorticoid receptor phosphorylated at serine 211, a modification known to enhance receptor activity. CONCLUSION: Our data support the hypothesis that mitogen-activated protein kinases influence the ability of certain malignant lymphoid cells to undergo apoptosis when treated with glucocorticoid. Activated/phosphorylated JNK and ERK appear to counteract corticoid-dependent apoptosis. Inhibiting these MAPKs restores corticoid sensitivity to a resistant clone of CEM cells. Forskolin, which activates the cAMP pathway, and rapamycin, which inhibits mTOR, also inhibit JNK. Further, the sensitizing treatments result in a largely dexamethasone-dependent increase in the total pool of glucocorticoid receptor phosphorylated at serine 211. The phospho-serine 211 receptor is known to be more potent in activating gene transcription and apoptosis. The interactive effects demonstrated here in reverting resistant cells to corticoid sensitivity could provide therapeutic clinical potential in the treatment of lymphoid malignancies

EFFECTS OF MANAGEMENT PRACTICES ON GRASSLAND BIRDS: LESSER PRAIRIE-CHICKEN

Information on the habitat requirements and effects of habitat management on grassland birds were summarized from information in more than 4,000 published and unpublished papers. A range map is provided to indicate the breeding distribution of Lesser Prairie-Chicken in the United States and southern Canada. Although birds frequently are observed outside the breeding range indicated, the maps are intended to show areas where managers might concentrate their attention. It may be ineffectual to manage habitat at a site for a species that rarely occurs in an area. The species account begins with a brief capsule statement, which provides the fundamental components or keys to management for the species. A section on breeding range outlines the current breeding distribution of the species in North America. The suitable habitat section describes the breeding habitat and occasionally microhabitat characteristics of the species, especially those habitats that occur in the Great Plains. Details on habitat and microhabitat requirements often provide clues to how a species will respond to a particular management practice. A table near the end of the account complements the section on suitable habitat, and lists the specific habitat characteristics for the species by individual studies. A special section on prey habitat is included for those predatory species that have more specific prey requirements. The area requirements section provides details on territory and home range sizes, minimum area requirements, and the effects of patch size, edges, and other landscape and habitat features on abundance and productivity. It may be futile to manage a small block of suitable habitat for a species that has minimum area requirements that are larger than the area being managed. The Brown-headed Cowbird (Molothrus ater) is an obligate brood parasite of many grassland birds. The section on cowbird brood parasitism summarizes rates of cowbird parasitism, host responses to parasitism, and factors that influence parasitism, such as nest concealment and host density. The impact of management depends, in part, upon a species’ nesting phenology and biology. The section on breeding-season phenology and site fidelity includes details on spring arrival and fall departure for migratory populations in the Great Plains, peak breeding periods, the tendency to renest after nest failure or success, and the propensity to return to a previous breeding site. The duration and timing of breeding varies among regions and years. Species’ response to management summarizes the current knowledge and major findings in the literature on the effects of different management practices on the species. The section on management recommendations complements the previous section and summarizes specific recommendations for habitat management provided in the literature. If management recommendations differ in different portions of the species’ breeding range, recommendations are given separately by region. The literature cited contains references to published and unpublished literature on the management effects and habitat requirements of the species. This section is not meant to be a complete bibliography; a searchable, annotated bibliography of published and unpublished papers dealing with habitat needs of grassland birds and their responses to habitat management is posted at the Web site mentioned below

Effects of Management Practices on Grassland Birds: Sprague’s Pipit

Sprague’s Pipit (Anthus spragueii): Breeding range Suitable habitat Area requirements Brown-headed Cowbird brood parasitism Breeding-season phenology and site fidelity Species’ response to management Management Recommendations Habitat Characteristic

Effects of Management Practices on Grassland Birds: Sprague’s Pipit

Sprague’s Pipit (Anthus spragueii): Breeding range Suitable habitat Area requirements Brown-headed Cowbird brood parasitism Breeding-season phenology and site fidelity Species’ response to management Management Recommendations Habitat Characteristic

Effects of Management Practices on Grassland Birds: Grasshopper Sparrow

Grasshopper Sparrow (Ammodramus savannarum): Breeding range Suitable habitat Area requirements Brown-headed Cowbird brood parasitism Breeding-season phenology and site fidelity Species’ response to management Management Recommendations Habitat Characteristic

Effects of Management Practices on Grassland Birds: Field Sparrow

Field Sparrow (Spizella pusilla): Breeding range Suitable habitat Area requirements Brown-headed Cowbird brood parasitism Breeding-season phenology and site fidelity Species’ response to management Management Recommendations Habitat Characteristic

Effects of Management Practices on Grassland Birds: Grasshopper Sparrow

Grasshopper Sparrow (Ammodramus savannarum): Breeding range Suitable habitat Area requirements Brown-headed Cowbird brood parasitism Breeding-season phenology and site fidelity Species’ response to management Management Recommendations Habitat Characteristic

Effects of Management Practices on Grassland Birds: Burrowing Owl

Burrowing Owl ( Speotyto cunicularia hypugaea): Breeding range Suitable habitat Prey habitat Area requirements Brown-headed Cowbird brood parasitism Breeding-season phenology and site fidelity Species’ response to management Management Recommendations Characteristic

Search for Fractional Charges in Water

Results are presented from a search for fractional charges in water from a variety of natural sources. About 30 000 water drops have been measured, comprising 51 μg of water and dissolved materials. No evidence for fractional charge was seen