The CXCR1 tail mediates beta1 integrin-dependent cell migration via MAP kinase signaling

In this study, we examined how IL-8 induces leukocyte migration on major beta1 integrin ligands derived from the extracellular matrix protein fibronectin. We assessed individual contributions of signaling by IL-8 receptors by transfection of CXCR1 and CXCR2 into rat basophilic leukemia (RBL) cells and human monocytic THP-1 cells. CXCR1 expressing cells migrated on the fibronectin ligands for alpha4beta1 and alpha5beta1 integrins in response to IL-8, whereas CXCR2 expressing cells did not. RBL cells expressing the chimeric CXCR1 receptor containing the cytoplasmic tail of CXCR2 had greatly blunted migration, while cells expressing the CXCR2 chimera with the tail of CXCR1 had augmented migration. Last, inhibitors of p38 and JNK MAP kinases blocked IL-8-induced migration in CXCR1+ cells. We conclude that IL-8 stimulated beta1 integrin-mediated leukocyte migration on fibronectin through CXCR1 is dependent on the C-terminal cytoplasmic domain of CXCR1 and subsequent p38 and JNK MAPK signaling.     

Chemical composition effects onto antimicrobial and antioxidant activities of propolis collected from different regions of Turkey

Chrysin, apigenin, flavonoids, flavanones, naringenin, ethyl oleate, 3-4-dimethoxy-cinnamic acid and 9-octadecenoic acid were the predominant components of propolis samples collected from different regions of Turkey. The extracts of P3 from Denizli-Ba?karci, P5 from Denizli and P7 from Tekirda? had effective antibacterial activities on Gram-negatives. Chrysin, which has antibacterial activity, was found to be high concentration. The extracts of P3, P2B from Aydin and P6 from Konya had much more effective antibacterial activities on Gram-positives. The total antioxidant activity increased with the increasing amount of extracts added to linoleic acid emulsion. All doses of propolis ethanol extract displayed antioxidant activity.     

Sacrificial limbs of sovereignty: disabled veterans, masculinity, and nationalist politics in Turkey

Over the last decade, disabled veterans of the Turkish Army who were injured while fighting against the Partiya Karkerên Kurdistan (PKK; Kurdistan Workers' Party) have become national icons and leading ultranationalist actors. While being valorized as sacrificial heroes in nationalist discourse, they have also confronted socioeconomic marginalization, corporeal otherness, and emasculation anxieties. Against this backdrop, disabled veterans' organizations have become the locus of an ultranationalist campaign against dissident intellectuals. Building on two years of ethnographic research with disabled veterans in Turkey, this article analyzes these processes through the analytical lens of the body. Locating the disabled veteran body at the intersection of state welfare practices, nationalist discourses on heroism and sacrifice, and cultural norms of masculinity and disability, I illustrate how disabled veterans' gendered and classed experiences of disability are hardened into a political identity. Consequently, I show how violence generates new modalities of masculinity and political agency through its corporeal effects.     

DNA repair genes polymorphism (<Emphasis Type="Italic">XPG</Emphasis> and <Emphasis Type="Italic">XRCC1</Emphasis>) and association of prostate cancer in a north Indian population

Prostate cancer is the most commonly diagnosed cancer in men worldwide and is the second leading cause of cancer related mortality. Genetic background may account for the difference in susceptibility of individuals to different diseases and the relationship between genetic polymorphism and some diseases has been extensively studied. There are several common polymorphisms in genes encoding DNA repair enzymes, some of these polymorphisms are reported to result in subtle structural alterations of the repair enzyme and modulation of the repair capacity. The aim of the present study was to analyze the effect of XPG Asp 1104His and XRCC1 Arg309Gln polymorphisms on risk of prostate cancer in north Indian population. Statistically significant increased risk of prostate cancer was observed on individuals that posses His/His genotype of XPG (OR 2.53, 95% CI 0.99–6.56, P = 0.031). In this study 150 prostate cancer diagnosed patients, 150 healthy controls and 150 BPH (benign prostate hyper plasia) were recruited from north Indian population. Moreover, individuals that carried the Gln/Gln genotype of XRCC1 also showed statistically increased risk of prostate cancer (OR 2.06, 95% CI 1.07–4.00, P = 0.033). The Asp/Asp of XPG and Gln/Gln of XRCC1 in combination showed statistically increased risk of prostate cancer in cases (OR 3.29, 95% CI 1.09–10.16, P = 0.032).     

Acute Doxorubicin insult in the mouse ovary is cell- and follicle-type dependent

Primary ovarian insufficiency (POI) is one of the many unintended consequences of chemotherapy faced by the growing number of female cancer survivors. While ovarian repercussions of chemotherapy have long been recognized, the acute insult phase and primary sites of damage are not well-studied, hampering efforts to design effective intervention therapies to protect the ovary. Utilizing doxorubicin (DXR) as a model chemotherapy agent, we defined the acute timeline for drug accumulation, induced DNA damage, and subsequent cellular and follicular demise in the mouse ovary. DXR accumulated first in the core ovarian stroma cells, then redistributed outwards into the cortex and follicles in a time-dependent manner, without further increase in total ovarian drug levels after four hours post-injection. Consistent with early drug accumulation and intimate interactions with the blood supply, stroma cell-enriched populations exhibited an earlier DNA damage response (measurable at 2 hours) than granulosa cells (measurable at 4 hours), as quantified by the comet assay. Granulosa cell-enriched populations were more sensitive however, responding with greater levels of DNA damage. The oocyte DNA damage response was delayed, and not measurable above background until 10-12 hours post-DXR injection. By 8 hours post-DXR injection and prior to the oocyte DNA damage response, the number of primary, secondary, and antral follicles exhibiting TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive granulosa cells plateaued, indicating late-stage apoptosis and suggesting damage to the oocytes is subsequent to somatic cell failure. Primordial follicles accumulate significant DXR by 4 hours post-injection, but do not exhibit TUNEL-positive granulosa cells until 48 hours post-injection, indicating delayed demise. Taken together, the data suggest effective intervention therapies designed to protect the ovary from chemotherapy accumulation and induced insult in the ovary must act almost immediately to prevent acute insult as significant damage was seen in stroma cells within the first two hours.     

Tissue biomarkers for prostate cancer radiation therapy

Prostate cancer is the most common cancer and second leading cause of cancer deaths among men in the United States. Most men have localized disease diagnosed following an elevated serum prostate specific antigen test for cancer screening purposes. Standard treatment options consist of surgery or definitive radiation therapy directed by clinical factors that are organized into risk stratification groups. Current clinical risk stratification systems are still insufficient to differentiate lethal from indolent disease. Similarly, a subset of men in poor risk groups need to be identified for more aggressive treatment and enrollment into clinical trials. Furthermore, these clinical tools are very limited in revealing information about the biologic pathways driving these different disease phenotypes and do not offer insights for novel treatments which are needed in men with poor-risk disease. We believe molecular biomarkers may serve to bridge these inadequacies of traditional clinical factors opening the door for personalized treatment approaches that would allow tailoring of treatment options to maximize therapeutic outcome. We review the current state of prognostic and predictive tissue-based molecular biomarkers which can be used to direct localized prostate cancer treatment decisions, specifically those implicated with definitive and salvage radiation therapy.     

“Shaping” of cell signaling via AKAP-tethered PDE4D: Probing with AKAR2-AKAP5 biosensor

Background

PKA, a key regulator of cell signaling, phosphorylates a diverse and important array of target molecules and is spatially docked to members of the A-kinase Anchoring Protein (AKAP) family. AKAR2 is a biosensor which yields a FRET signal in vivo, when phosphorylated by PKA. AKAP5, a prominent member of the AKAP family, docks several signaling molecules including PKA, PDE4D, as well as GPCRs, and is obligate for the propagation of the activation of the mitogen-activated protein kinase cascade from GPCRs to ERK1,2.

Results

Using an AKAR2-AKAP5 fusion ??biosensor??, we investigated the spatial-temporal activation of AKAP5 undergoing phosphorylation by PKA in response to ??-adrenergic stimulation. The pattern of PKA activation reported by AKAR2-AKAP5 is a more rapid and spatially distinct from those ??sensed?? by AKAR2-AKAP12. Spatial-temporal restriction of activated PKA by AKAP5 was found to ??shape?? the signaling response. Phosphatase PDE4D tethered to AKAP5 also later reverses within 60?s elevated intracellular cyclic AMP levels stimulated by ??-adrenergic agonist. AKAP12, however, fails to attenuate the rise in cyclic AMP over this time. Fusion of the AKAP5 PDE4D-binding-domain to AKAP12 was found to accelerate a reversal of accumulation of intracellular cyclic AMP.

Conclusion

AKAPs, which are scaffolds with tethered enzymes, can ??shape?? the temporal and spatial aspects of cell signaling.     

"Shaping" of cell signaling via AKAP-tethered PDE4D: Probing with AKAR2-AKAP5 biosensor

ABSTRACT: BACKGROUND: PKA, a key regulator of cell signaling, phosphorylates a diverse and important array of target molecules and is spatially docked to members of the A-kinase Anchoring Protein (AKAP) family. AKAR2 is a biosensor which yields a FRET signal in vivo, when phosphorylated by PKA. AKAP5, a prominent member of the AKAP family, docks several signaling molecules including PKA, PDE4D, as well as GPCRs, and is obligate for the propagation of the activation of the mitogen-activated protein kinase cascade from GPCRs to ERK1,2. RESULTS: Using an AKAR2-AKAP5 fusion "biosensor", we investigated the spatial-temporal activation of AKAP5 undergoing phosphorylation by PKA in response to beta-adrenergic stimulation. The pattern of PKA activation reported by AKAR2-AKAP5 is a more rapid and spatially distinct from those "sensed" by AKAR2-AKAP12. Spatial-temporal restriction of activated PKA by AKAP5 was found to "shape" the signaling response. Phosphatase PDE4D tethered to AKAP5 also later reverses within 60 s elevated intracellular cyclic AMP levels stimulated by beta-adrenergic agonist. AKAP12, however, fails to attenuate the rise in cyclic AMP over this time. Fusion of the AKAP5 PDE4D-binding-domain to AKAP12 was found to accelerate a reversal of accumulation of intracellular cyclic AMP. CONCLUSION: AKAPs, which are scaffolds with tethered enzymes, can "shape" the temporal and spatial aspects of cell signaling.