Intergroup resource allocation among children from minority and majority groups in three settings of former conflict.

Intergroup resource allocation was examined among 333 children aged 7-11 (51.9% female) within three settings of former intergroup conflict (January-June 2021). Children represented both ethno-religious minority and majority groups (Republic of North Macedonia: Albanians, Macedonians; Croatia: Serbs, Croats; Northern Ireland: Catholics, Protestants), from predominantly White and middle-class families. Ingroup bias in average resource allocation amounts was demonstrated by both minority and majority children, across settings, in the context of novel targets (historic conflict rivals). Majority children were also more likely to give equally (which maintains the status quo) than minority children. Giving equally increased with age for both minority and majority children, despite being in "zero-sum," conflict settings. Equitable intergroup resource allocation in such settings has implications for conflict transformation.

Validation of a questionnaire exploring patient attitudes towards bedside teaching.

BACKGROUND: Bedside teaching (BST) facilitates medical education and has reduced in practice, often due to patient-related concerns. This study aimed to validate a questionnaire exploring patients attitudes towards BST. METHODS: International guidelines for questionnaire development were followed. Seven steps were included: literature review, patient interviews, development of clear and understandable items, expert validation, cognitive interviewing and pilot testing. Statistical analyses included exploratory factor analysis, internal consistency, investigation of demographic influences and discriminant validity across subscales. RESULTS: Following the literature review, 32 interviews were conducted. Potential items were developed, reviewed and adapted. Experts in medical education and statistics reviewed the draft questionnaire. Fifteen patients consented to cognitive testing and 401 consenting patients completed the final version. The median age of participants was 35 years of age (range: 18 to 70 years). Participants included women attending for antenatal (40%), postnatal (32%) and gynaecology issues (28%). Just under one third (29%) had taken part in medical student teaching previously. Statistical analyses found a two-factor solution, consisting of Educate medical professionals and Conditions for participation subscales with good internal consistency; responses did not vary by age or education. Participants who had opted-in for teaching in the ward and bedside endorsed higher levels of Educate medical professionals, suggesting discriminant validity. A majority of patients (> 92%) reported that they were happy to be involved in BST. Patients believed that they should not be asked to participate in BST should they feel stressed or unwell (68.2%). CONCLUSION: This study shows extensive patient support for BST, independent of age or education. The desire to educate is a strong motivating factor. This strong support by patients for BST is an area that medical schools and universities can potentially develop. Future versions of this questionnaire may include virtual bedside teaching, in the context of social distancing.

Palliative care in Yorkshire, UK 1987-2008: survival and mortality in a hospice.

OBJECTIVE: To provide new epidemiological evidence base of information on models of hospice care for children and young adults. DESIGN: Retrospective cohort study of children referred to a hospice. SETTING: Martin House Children's and Young Person's Hospice in Boston Spa, North Yorkshire, UK. PARTICIPANTS: All children who had been referred for care at Martin House Children's Hospice since it opened in August 1987, until May 2008. MAIN OUTCOME MEASURES: Demographic profiles and survival times overall and by diagnostic group classified by the Association of Children's Palliative Care (ACT) Diagnostic Categories, calculated using the Kaplan- Meier and log rank pair-wise methodology. RESULTS: Over a 20-year period, 1554 children aged from birth to 19 years were referred to Martin House, of whom 89.5% (mean age 7.45 years) were accepted. The deprivation profile, referral source and distribution of diagnoses of these children have changed over time with recently increasing numbers of non-progressive disorders (ACT category 4). The ethnicity profile has changed with an increase in the numbers of South Asian children. The overall mean survival time was 5.6 years (95% CI 5.1 to 6.1) but this differed by ACT category. Diagnostic category was significantly associated with differing survival patterns. CONCLUSIONS: There are a disproportionate number of children from areas of higher deprivation being referred for palliative care services. There has been a recent increase in the number of children from South Asian families being referred to palliative care services in Yorkshire. Survival times for children and young people receiving care from a hospice can vary from hours and days to more than 20 years.

Red light regulation of ethylene biosynthesis and gravitropism in etiolated pea stems.

During gravitropism, the accumulation of auxin in the lower side of the stem causes increased growth and the subsequent curvature, while the gaseous hormone ethylene plays a modulating role in regulating the kinetics of growth asymmetries. Light also contributes to the control of gravitropic curvature, potentially through its interaction with ethylene biosynthesis. In this study, red-light pulse treatment of etiolated pea epicotyls was evaluated for its effect on ethylene biosynthesis during gravitropic curvature. Ethylene biosynthesis analysis included measurements of ethylene; the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC); malonyl-conjugated ACC (MACC); and expression levels of pea ACC oxidase (Ps-ACO1) and ACC synthase (Ps-ACS1, Ps-ACS2) genes by reverse transcriptase-polymerase chain reaction analysis. Red-pulsed seedlings were given a 6 min pulse of 11 micromoles m-2 s-1 red-light 15 h prior to horizontal reorientation for consistency with the timeline of red-light inhibition of ethylene production. Red-pulse treatment significantly reduced ethylene production and MACC levels in epicotyl tissue. However, there was no effect of red-pulse treatment on ACC level, or expression of ACS or ACO genes. During gravitropic curvature, ethylene production increased from 60 to 120 min after horizontal placement in both control and red-pulsed epicotyls. In red-pulsed tissues, ACC levels increased by 120 min after horizontal reorientation, accompanied by decreased MACC levels in the lower portion of the epicotyl. Overall, our results demonstrate that ethylene production in etiolated epicotyls increases after the initiation of curvature. This ethylene increase may inhibit cell growth in the lower portion of the epicotyl and contribute to tip straightening and reduced overall curvature observed after the initial 60 min of curvature in etiolated pea epicotyls.

The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias.

Stretch-activated ion channels have been identified as transducers of mechanoelectric coupling in the heart, where they may play a role in arrhythmogenesis. The role of the cytoskeleton in ion channel control has been a topic of recent study and the transmission of mechanical stresses to stretch-activated channels by cytoskeletal attachment has been hypothesized. We studied the arrhythmogenic effects of stretch in 16 Langendorff-perfused rabbit hearts in which we pharmacologically manipulated the microtubular network of the cardiac myocytes. Group 1 (n=5) was treated with colchicine, which depolymerizes microtubules, and Group 2 (n=6) was treated with taxol, which polymerizes microtubules. Stretch-induced arrhythmias were produced by transiently increasing the volume of a fluid-filled left ventricular balloon with a volume pump driven by a computer-controlled stepper motor. Electrical events were recorded by a contact electrode which provided high-fidelity recordings of monophasic action potentials and stretch-induced depolarizations. The probability of eliciting a stretch-induced arrhythmia increased (0.22+/-0.11 to 0.62+/-0.19, p=0.001) in hearts treated with taxol (5 microM), whereas hearts treated with colchicine (100 microM) showed no statistically significant change. We conclude that proliferation of microtubules increased the arrhythmogenic effect of transient left ventricle diastolic stretch. This result indicates a possible mode of arrhythmogenesis in chemotherapeutic patients and patients exhibiting uncompensated ventricular hypertrophy. The data would indicate that the cytoskeleton represents a possible target for antiarrhythmic therapies.

Transcription factor phosphorylation by pp90(rsk2). Identification of Fos kinase and NGFI-B kinase I as pp90(rsk2).

The in vitro phosphorylation of transcription factors by growth factor-activated protein kinases has resulted in the discovery of a number of activities whose identities and relationships to one another are unclear. Fos kinase is a growth factor-stimulated serine/threonine protein kinase that phosphorylates c-Fos at serine 362 within the carboxyl-terminal regulatory domain. Fos kinase activation is dependent on p21(ras) and mitogen-activated protein kinase/ERK kinase kinase (MEK) activity and is independent of phosphatidylinositol 3-kinase activity. We have purified Fos kinase by affinity chromatography using the Sepharose-linked protein kinase inhibitor, bisindolylmaleimide (BIM). Fos kinase has an apparent molecular mass of 88 kDa, and mass spectrophotometric analysis of the isolated protein showed that it produced tryptic fragments identical to those predicted for pp90(rsk2). Fos kinase isolated from nerve growth factor-stimulated PC12 cells is indistinguishable from NGFI-B kinase I, based on their chromatographic behavior, substrate specificities, and relative sensitivity to BIM. Furthermore, we have distinguished Fos kinase from calcium/cAMP response element-binding protein (CREB) kinase. Therefore, Fos kinase and NGFI-B kinase I and pp90(rsk2) represent the same protein kinase species. Moreover, we report that pp90(rsk2) exists within nerve growth factor-stimulated PC12 cells as two chromatographically and immunologically distinct species. Finally, we demonstrate that CREB kinase is distinct from pp90(rsk2).

The effect of music in the postanesthesia care unit on pain levels in women who have had abdominal hysterectomies.

Management of pain in the immediate postoperative period is a major concern of postanesthesia nurses. Music is a nursing intervention with the potential to decrease patient perception of pain in the PACU. The purpose of this study was to examine the effect of the use of music on the level of patient pain in the immediate postoperative period. A quasi-experimental study design was used with three study groups. All patients scheduled for elective abdominal hysterectomies using a general anesthesia technique were eligible for participation in the study. The setting is a PACU in a community hospital in a suburban area. Subjects were asked to rate their pain level every 15 minutes while in the PACU using two valid and reliable measures, a verbal pain rating scale and a graphic numeric pain intensity scale. Repeated measures of analysis of variance showed no differences in level of pain between groups or over time.

New South Wales population-based birthweight percentile charts.

OBJECTIVE: To derive newborn percentile charts using NSW population and hospital-based data. METHODOLOGY: Birthweight data for liveborn singleton infants were obtained from the New South Wales Midwives Data Collection (MDC) from 1990 to 1994 inclusive (n = 422139). Data were also collected from King George V Hospital (KGV) for liveborn singleton infants less than 35 weeks of gestation for 1982-89 inclusive, and for all gestations for 1990-95 inclusive (n = 30610). Birthweight percentiles were derived using the MDC data separately for males and females. Head circumference (n = 29090) and birth length percentiles (n = 26973) were derived from the KGV data. RESULTS: The charts derived from MDC data had generally higher percentiles than previously published charts. These represent the largest Australian population-based study published to date. CONCLUSIONS: Periodic review of newborn growth charts is recommended because of changing ethnic and socio-economic factors.

Newly identified stress-responsive protein kinases, Krs-1 and Krs-2.

The activation of protein kinases is a frequent response of cells to treatment with growth factors, chemicals, heat shock, or apoptosis-inducing agents. However, when several agents result in the activation of the same enzymes, it is unclear how specific biological responses are generated. We describe here two protein kinases that are activated by a subset of stress conditions or apoptotic agents but are not activated by commonly used mitogenic stimuli. Purification and cloning demonstrate that these protein kinases are members of a subfamily of kinases related to Ste20p, a serine/threonine kinase that functions early in a pheromone responsive signal transduction cascade in yeast. The specificity of Krs-1 and Krs-2 activation and their similarity to Ste20p suggest that they may function at an early step in phosphorylation events that are specific responses to some forms of chemical stress or extreme heat shock.

Calcium- and sodium-dependent modulation of stretch-induced arrhythmias in isolated canine ventricles.

Gadolinium-sensitive stretch-activated channels have been implicated in the process of mechanotransduction signaling of ventricular myocardium. Such channels nonspecifically transport Na+ and Ca2+ in the inward direction. We tested the hypothesis that Na+ and Ca2+ influx are important in the genesis of stretch-induced arrhythmias (SIAs) in an isolated, blood-perfused canine ventricle. To elicit SIAs, left ventricular volume was transiently increased in early diastole using a computerized servo-pump system. Monophasic action potential recordings revealed stretch-induced depolarizations (SIDs) that preceded the arrhythmias. In five ventricles, raising the perfusate Ca2+ concentration from 1 to 3 mM increased ventricular sensitivity to SIAs, manifested by a decrease in the volume change required to precipitate an arrhythmia 50% of the time (delta V50) from 19.5 +/- 2.7 to 15.2 +/- 1.9 ml (P < 0.05). When the perfusate Na+ concentration was decreased from 150 to 90 mM in seven ventricles, delta V50 greatly increased (31.1 +/- 14.4 vs. 17.7 +/- 5.3 ml, P < 0.05), and SID amplitude decreased by 47% (P = 0.002). The suppression of SIAs with low extracellular Na+ is unlikely to be mediated by voltage-gated Na+ channels because lidocaine (5 mg/dl) did not alter SID amplitude. Thus the transsarcolemmal Na+ gradient (and probably that of Ca2+) modulates the amplitude of SIDs, which, in turn, initiate SIAs. These data provide initial evidence that Na+ and Ca2+ help mediate the mechanotransduction processes that underly the genesis of SIAs.

Mechanical characteristics of tachycardia-induced left-ventricular failure as evaluated in isolated dog hearts.

Left ventricles of control dog hearts and dog hearts failing due to chronic tachycardia were examined in vivo by echocardiography for systolic function and size, then subsequently studied with an isolated-heart system (artificial perfusion, artificial loading). During 3 weeks of tachycardia (250 bt/min), area ejection fraction fell by 58%, while end-diastolic transverse area increased by 56% (measurements at 120 bt/min). Judging from post-perfusion left-ventricular weights, the dilation occurred with no hypertrophy, raising the question whether the failure model may be associated with anabolic dysfunction. End-diastolic pressure-volume (P-V) relations occurred at higher volumes in failing chambers than in controls, and this was marked by increases in two indices of chamber size (candidate reference volumes): the volume resulting in a diastolic stress of 16 g/cm2, and the volume at which the nearly straight, low-stiffness segment of the end-diastolic P-V relation meets the upward bending, high-stiffness segment. Developed P-V relations of failing chambers were shifted to higher volumes and to lower pressures, the lower pressures being due more to reduced stress-developing ability (contractility) than to reduced wall/cavity ratio (pressure/stress ratio). On average, shortening ability (normalized difference between reference volume and extrapolated volume-axis intercept, i.e., apparent ejection fraction from reference volume in absence of afterload) was not different from that of controls. Isovolumic pressure waves of the failing and dilated chambers were of almost normal duration and shape, extending further the range of conditions where isovolumic pressure can be predicted by fitting a model isovolumic wave function to the isovolumic phases of ejecting beats.

Effect of ryanodine on the initiation and perpetuation of stretch-induced arrhythmias in isolated canine ventricle.

Ventricular arrhythmias can be initiated by a mechanism of transient diastolic dilation. To test the hypothesis that Ca2+ release from sarcoplasmic reticulum (SR) is important in initiation of such stretch-induced arrhythmias (SIAs), we studied effects of ryanodine in an isolated canine heart model. Arrhythmias were induced by a computerized ventricular volume servo-pump system that transiently increased left ventricular volume by precise amounts (delta V) during diastole. The probability of eliciting an SIA (PSIA) was compared at the minimum delta V that resulted in PSIA of > or = 90% under baseline conditions. Block of SR Ca2+ release with 10(-5) M ryanodine in 11 ventricles produced mild inhibition of SIAs, reducing PSIA by 19.4% (P = 0.039). Because ryanodine produces leakage of SR Ca2+ at low concentration and block of SR Ca2+ release at high concentration, ryanodine concentration was varied from 10(-9) to 10(-5) M in six ventricles. Ryanodine had minimal effect on PSIA over this concentration range. In six ventricles with elevated intracellular Ca2+ produced by pretreatment with 0.1-0.3 microM strophanthidin, 10(-5) M ryanodine did not significantly reduce PSIA. Probability of inducing ventricular pairs or nonsustained ventricular tachycardia was greater in strophanthidin-treated ventricles than in controls, but induction of these repetitive ventricular beats in the strophanthidin group was virtually abolished by addition of 10(-5) M ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)

Initiation of ventricular extrasystoles by myocardial stretch in chronically dilated and failing canine left ventricle.

BACKGROUND: Stretch-induced arrhythmias (SIAs) can be elicited in normal canine left ventricles by transient diastolic dilatation. Since clinically important ventricular arrhythmias arise most commonly in failing and dilated ventricles, we hypothesized that the arrhythmogenic effect of transient diastolic stretch would be enhanced in chronically dilated failing canine hearts. METHODS AND RESULTS: Heart failure was induced in seven dogs by right ventricular pacing at 250 min-1 for 20.2 +/- 1.6 days. Left ventricular (LV) mechanical properties were measured in vivo with serial echocardiograms in these seven dogs with the dogs awake and tranquilized to confirm the development of LV dilation and failure. By the third week of pacing, average short-axis area ejection fraction decreased by 64.3% (P < .001) as end-diastolic and end-systolic diameters increased by 25.9% and 50.7%, respectively (P < .001). After heart failure was established, the hearts were harvested and in vitro data were obtained as an isolated, blood-perfused ventricle preparation. A computerized servo pump system connected to an LV intracavitary balloon was used to measure and control LV volume. Results were compared with in vitro data obtained from eight ventricles not subjected to pacing (controls). LV contractility, quantitated in vitro as the slope of the peak isovolumic pressure-volume relation (Emax) normalized to LV cavity size, was much lower in the heart failure group than in controls (182 +/- 18 versus 365 +/- 38 mm Hg, P < .001). In all isolated hearts, SIAs were induced using an electromechanical stimulation protocol in which eight paced beats at 2 Hz were followed by a transient increase in LV volume during early diastole. Prestretch volume (Vi) was selected to yield end-diastolic pressures of 4 to 8 mm Hg in all hearts. The fractional increase in LV volume (delta V) that produced SIAs 50% of the time (delta V 50/Vi) was smaller in failing hearts than in controls (0.78 +/- 0.04 versus 1.18 +/- 0.17, P = .009), indicating an increased sensitivity to SIAs in the failing hearts. Although ventricular pairs were occasionally induced in both groups, the great majority of the arrhythmias induced in both groups were single extrasystoles, and nonsustained runs of ventricular tachycardia were never elicited in either group. LV end-diastolic and peak stretch pressures were similar in the two groups, but LV end-diastolic wall stress was higher by 35.7% (P = .029) in the dilated failing ventricles because LV hypertrophy, which tends to normalize wall stress as the heart dilates, did not occur during the 3 weeks of pacing. For stretch stimuli of comparable arrhythmogenic effectiveness, peak LV wall stress during stretch was similar in the two groups, whereas the fractional increase in volume was significantly smaller in the heart failure group, indicating impaired viscoelastic properties in the failing ventricles. In five control ventricles, acute exposure to 0.5 mumol/L dobutamine increased ventricular sensitivity to the induction of SIAs, as shown by a decrease in delta V50/Vi from 1.27 +/- 0.16 to 1.06 +/- 0.11 (P = .04). CONCLUSIONS: Altered mechanical properties and/or neurohumoral adaptations associated with chronic dilation and failure predispose the ventricle to induction of ventricular extrasystoles by transient LV diastolic stretch.

The vaccination status of aboriginal children in the North Coast Health Region of New South Wales.

OBJECTIVE: To determine the vaccination status of Aboriginal children resident in the North Coast Health Region of NSW. DESIGN: Cross-sectional descriptive study. SETTING AND PARTICIPANTS: The vaccination status of Aboriginal children aged 4 months to 11 years and resident in selected villages/isolated communities, small and large towns in the North Coast Health Region of NSW was determined by review of vaccination records. Data were obtained from general practitioners, the Aboriginal Health Service, Community Health Centres and Local Government Councils. MAIN OUTCOME MEASURES: Vaccination status according to the childhood immunisation schedule recommended by the National Health and Medical Research Council, defined as fully or partially documented, with a generous lag time. RESULTS: The study population comprised 1179 children--55% of the estimated Aboriginal population under 12 years of age in the North Coast Health Region. Data collection on Sabin vaccine was incomplete and was not included in the analysis. Of 1094 children whose records were analysed, 9% had fully documented and 27% fully or partially documented evidence of up-to-date vaccinations. For measles vaccination, 28% of children aged 18 months or more had fully documented and 35% fully or partially documented evidence of vaccination. There was no fully documented evidence of any vaccinations for 52% of children. CONCLUSION: The vaccination status of Aboriginal children in the North Coast Health Region is poor. The 1989-1990 National Health Survey showed overall vaccination rates for NSW and Australia to be more than twice those found for this population.

Activation of a novel serine/threonine kinase that phosphorylates c-Fos upon stimulation of T and B lymphocytes via antigen and cytokine receptors.

Ligation of Ag receptors in T and B lymphocytes initiates signal transduction cascades which alter the expression of genes that regulate cellular proliferation and differentiation. The transmission of signals from the membrane to the nucleus is mediated principally through the action of protein tyrosine and serine/threonine kinases. We have identified and characterized a novel serine/threonine kinase that phosphorylated the proto-oncogene product, c-Fos, and is termed Fos kinase. Fos kinase was rapidly activated after ligation of the CD3 and CD2 receptors in Jurkat and normal human T lymphocytes and in response to IL-6 and anti-IgM in the human B cell lines AF10 and Ramos, respectively. The phorbol ester, PMA, was also a potent inducer of Fos kinase activity in all of the above populations, suggesting that PKC plays a role in the regulation of this enzyme. Fos kinase phosphorylates c-Fos at a site near the C-terminus, as well as a peptide derived from this region (residues 359-370, RKGSSSNEPSSD), and Fos peptide competitively inhibited c-Fos phosphorylation. Fos kinase was shown to be distinct from other identified serine/threonine kinases, including protein kinase A, protein kinase C, casein kinase II, MAP kinases, p70S6K and p90RSK. Fos kinase was purified by anion exchange chromatography and exhibited an apparent M(r) = 65,000 and isoelectric point = 6.1. Fos kinase may play a role in transcriptional regulation through its capacity to phosphorylate c-Fos at a site required for expression of the transcriptional transrepressive activity of this molecule. Moreover, its rapid activation suggests it may have a wider role within signal transduction cascades in lymphocytes.

Characteristics of left-ventricular isovolumic pressure waves in isolated dog hearts.

The peak pressure which a chamber would develop in isovolumic contraction at end-diastolic distention (peak source pressure) is an expression of contractile vigor and a determinant of systolic performance. One can predict source pressure of an ejecting beat by fitting its isovolumic phases with a model isovolumic-wave function. Characteristics of the left-ventricular isovolumic pressure wave (amplitude, duration, shape) were studied in isolated, perfused, artificially loaded dog hearts, where strictly isovolumic conditions could be obtained over a wide range of cavity volumes at constant heart rate and approximately constant contractile state. The characterization involved two steps: (1) beginning and ending points were identified by a transition-locating algorithm, and (2) Fourier analysis was performed on points in between. The amplitude of the isovolumic pressure wave increased with cavity volume as expected, the duration of contraction increased with cavity volume, and the shape of the wave (normalized Fourier coefficients) depended slightly on the cavity volume. Duration of contraction declined slightly with increasing heart rate, but the shape of the isovolumic pressure wave was independent of heart rate. The mean shape was similar to that found in dog hearts subjected to one-beat aortic-root clamping in vivo-the wave being less sharply peaked than a cosine wave and tilted to the left because relaxation was slower than contraction. When ejecting beat duration declined linearly with increasing ejection fraction. This relation could be used to predict the duration of the isovolumic beat corresponding to the duration of an ejecting beat. Source pressure could then be predicted by fitting a model isovolumic wave of predicted duration to the isovolumic contraction phase of the ejecting beat. In 270 comparisons, the ratio of predicted peak source pressure to observed peak source pressure was 1.04 +/- 0.10 (SD). This method provides a reasonably accurate prediction of an important determinant of systolic performance.

A bryostatin-sensitive protein kinase C required for nerve growth factor activity.

Nerve growth factor (NGF) stimulates rat pheochromocytoma cells (PC12) to differentiate into a neuronal-like cell that exhibits neurite extensions. The role of protein kinase C in signal transduction has been examined in PC12 cells treated with phorbol 12-myristate 13-acetate (PMA) and bryostatin, a macrocyclic lactone that activates protein kinase C at both the nuclear and the plasma membranes [Hocevar, B. A., & Fields, A. P. (1991) J. Biol. Chem. 266, 28-33]. In contrast to PMA down-regulation [Reinhold, D. S., & Neet, K. E. (1989) J. Biol. Chem. 264, 3538-3544], chronic (24 h) treatment with bryostatin blocked the formation of neurites in response to NGF or basic fibroblast-derived growth factor stimulation, but, like PMA, bryostatin did not block the induction of c-fos or c-jun protooncogenes by NGF. Chronic bryostatin treatment down-regulated protein kinase C activity in the cytosolic, membrane, and nuclear fractions. Acute (60 min) bryostatin or NGF treatment activated cytosolic and nuclear protein kinase C activity, suggesting possible translocation to the nucleus. Bryostatin did not induce neurite outgrowth, either alone or in combination with PMA. Thus, the bryostatin-sensitive protein kinase C is distinct from PMA- or K252a-sensitive kinases previously described. The bryostatin-sensitive protein kinase C is necessary, but not sufficient, for neurite outgrowth and acts in the nucleus in a manner independent of c-fos and c-jun transcription.

Isolation and characterization of a nerve growth factor-regulated Fos kinase from PC12 cells.

Nerve growth factor (NGF) treatment of PC12 cells activates a protein kinase that phosphorylates c-Fos protein at a site near its C terminus, as well as a peptide corresponding to a C-terminal region of c-Fos (Taylor, L. K., Marshak, D. R., and Landreth, G. E. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 368-372). This serine/threonine kinase, termed Fos kinase, has been purified > 24,000-fold through five column steps to near homogeneity and is shown to be a 37-kDa protein as determined by SDS-polyacrylamide gel electrophoresis (PAGE) with a pI = 6.0. Fos kinase is distinguishable from previously characterized NGF-regulated kinases by its chromatographic behavior, its response to specific kinase inhibitors, and its substrate specificity. The concentration of NGF required to activate Fos kinase is consistent with signaling from the high affinity NGF receptor. Fos kinase phosphorylates c-Fos at its C terminus as indicated by competitive inhibition with a peptide corresponding to C-terminal phosphorylation sites and lack of phosphorylation of a C-terminal deletion mutant of c-Fos. Hyperphosphorylation of c-Fos in vivo, as detected by reduced electrophoretic mobility of c-Fos, is induced by the same ligands which activate Fos kinase. Moreover, Fos kinase phosphorylation of c-Fos in vitro results in a similar electrophoretic mobility shift, demonstrating that Fos kinase may be responsible for growth factor-stimulated alterations in mobility on SDS-PAGE and phosphorylation of this transcription factor. The ability of this unique growth factor-responsive kinase to phosphorylate c-Fos at its C terminus, a region essential for the transrepressive properties of c-Fos, suggests that Fos kinase may play a role in the regulation of the transcriptional repressive activity of c-Fos.