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At least 181 records · Page 10Linked to original sources
PubMed2004

Aberrant gating of photic input to the suprachiasmatic circadian pacemaker of mice lacking the VPAC2 receptor.

VIP acting via the VPAC(2) receptor is implicated as a key signaling pathway in the maintenance and resetting of the hypothalamic suprachiasmatic nuclei (SCN) circadian pacemaker; circadian rhythms in SCN clock gene expression and wheel-running behavior are abolished in mice lacking the VPAC(2) receptor (Vipr2(-/-)). Here, using immunohistochemical detection of pERK (phosphorylated extracellular signal-regulated kinases 1/2) and c-FOS, we tested whether the gating of photic input to the SCN is maintained in these apparently arrhythmic Vipr2(-/-) mice. Under light/dark and constant darkness, spontaneous expression of pERK and c-FOS in the wild-type mouse SCN was significantly elevated during subjective day compared with subjective night; no diurnal or circadian variation in pERK or c-FOS was detected in the SCN of Vipr2(-/-) mice. In constant darkness, light pulses given during the subjective night but not the subjective day significantly increased expression of pERK and c-FOS in the wild-type SCN. In contrast, light pulses given during both subjective day and subjective night robustly increased expression of pERK and c-FOS in the Vipr2(-/-) mouse SCN. Although photic stimuli activate intracellular pathways within the SCN of Vipr2(-/-) mice, they do not engage the core clock mechanisms. The absence of photic gating, together with the general lack of overt rhythms in circadian output, strongly suggests that the SCN circadian pacemaker is completely dysfunctional in the Vipr2(-/-) mouse.

Animals↗
PubMed2002

Role of platelet-derived growth factor receptor-mediated signal transduction in myocardial hypertrophy of spontaneously hypertensive rats.

The role of platelet-derived growth factor (PDGF) receptor-mediated signal transduction in myocardial hypertrophy of spontaneously hypertensive rats (SHR) was investigated. The protein expressions of PDGF beta receptor and extracellular signal-regulated kinase 1/2 (ERK 1/2) and the level of phosphorylated ERK 1/2 (pERK 1/2) in cardiac tissues from 4- and 12-week-old SHR and their age-matched normotensive control Wistar-Kyoto rats (WKY) were examined by Western blot analysis. The results showed that arterial systolic and diastolic blood pressure, +/-dp/dt(max) and the ratio of left ventricular weight to body weight were unchanged in 4-week-old SHR, while they were increased significantly in 12-week-old SHR as compared with those of age-matched WKY. There were no differences in PDGF beta receptor, pERK 1/2, and ERK 1/2 between 4-week-old WKY and SHR. The expression of PDGF beta receptor of 12-week-old SHR was significantly increased by 32.77% (P<0.05) as compared with that of age-matched WKY. Although the expression of ERK 1/2, the downstream signal molecule of PDGF receptor-mediated signal transduction pathway, was unchanged, the level of pERK 1/2, the active form of ERK 1/2, was increased by 19.6% (P=0.01) in 12-week-old SHR. To further elucidate the effect of PDGF beta receptor on cardiomyocyte growth and the relation between PDGF beta receptor and ERK 1/2 activity, (3)H leucine incorporation assay and immunoblotting analysis of pERK 1/2 were performed after cultured neonatal rat cardiomyocytes were stimulated with PDGF-BB. It was shown that (3)H leucine incorporation and pERK 1/2 level were significantly increased after PDGF-BB stimulation. These findings suggest that PDGF beta receptor may play an important role in the myocardial hypertrophy of spontaneously hypertensive rats.

Animals↗
PubMed2001

Nerve growth factor modulates the activation status and fast axonal transport of ERK 1/2 in adult nociceptive neurones.

Mature dorsal root ganglion cells respond to neurotrophins, and the intracellular signalling pathways activated by neurotrophins have been characterized in vitro. We have now used immunocytochemistry and Western blots to examine the expression and activation of extracellular signal-regulated protein kinase-1/2 (ERK) in rat dorsal root ganglion cells in vivo, using antisera to total (tERK) and phosphorylated (pERK) forms. This has revealed a number of novel findings. tERK immunoreactivity is present in most dorsal root ganglion cells but is expressed most strongly in small (nociceptive) cells and, surprisingly, is absent in a population of large cells that expressed trkB or trkC but mainly lack p75(NTR) immunoreactivity. In contrast pERK is prominent in a few trkA cells and in satellite glial cells, and is further increased by NGF treatment. tERK and pERK both undergo fast anterograde and retrograde axonal transport, indicated by accumulation at a sciatic nerve ligature, and NGF reduces the level of retrograde pERK transport.

Aging↗
PubMed2006

Role of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways downstream molecules, phosphorylated extracellular signal-regulated kinase, and phosphorylated AKT in colorectal cancer-a tissue microarray-based approach.

Tumor budding is defined as dedifferentiated cancer cells at the invasive margin of colorectal cancer (CRC) and correlates with a worse prognosis. The invasive margin and tumor budding are normally not present in a superficial diagnostic biopsy specimen. The aim of this study was to investigate the expression/overexpression of 2 downstream molecules of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways, phosphorylated AKT (pAKT) and phosphorylated extracellular signal-regulated kinase (pERK), in areas of CRC away from the invasive margin and determining if these variables were predictive of tumor budding or prognosis. A series of 1420 unselected, nonconsecutive CRC resections were subdivided into 3 groups: (1) DNA mismatch repair (MMR) proficient, (2) MLH1-negative, and (3) presumed HNPCC. Immunohistochemical analysis of pAKT and pERK expression (0% versus > 0%) and overexpression (increasing percentage of positivity) was performed using the tissue microarray technique. The results were correlated with clinicopathologic parameters. Fifty-seven samples of normal colon mucosa were included as a control group. Nuclear pERK expression (P = .008) was associated with presence of tumor budding in the MMR-proficient, but not in the MLH1-negative and presumed-HNPCC groups. In contrast, cytoplasmic pAKT overexpression was associated with early T stage (P = .04), early N stage (P = .02), and absence of tumor budding (P = .03) only in the MLH1-negative group. There was no association between pERK or pAKT and clinicopathologic parameters in the HNPCC group. Dysregulation of the mitogen-activated protein kinase pathway is likely to be implicated in the mechanism of tumor budding only in MMR-proficient CRC, whereas the phosphoinositide 3-kinase/AKT pathway is associated with early stage in MLH1-negative CRC.

Adenocarcinoma↗
PubMed2004

Oxidative injury to the endoplasmic reticulum in mouse brains after transient focal ischemia.

Oxidative damage to the endoplasmic reticulum (ER) could be involved in ischemic neuronal cell death because this organelle is susceptible to reactive oxygen species. Using wild-type mice and copper/zinc-superoxide dismutase (SOD1) transgenic mice, we induced focal cerebral ischemia and compared neuronal degeneration and ER stress, that is, phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and RNA-dependent protein kinase-like ER eIF2alpha kinase (PERK). We found that neurons with severe and prolonged phosphorylation of eIF2alpha and PERK underwent later degeneration, and that this was partially prevented by SOD1 overexpression. Signals for superoxide production and phospho-PERK were colocalized, which further indicates a pivotal role for superoxide in ER damage. We investigated the molecular mechanisms of oxidative ER stress and found that detachment of glucose-regulated protein 78 from PERK was the key step. We conclude that ER damage is involved in oxidative neuronal injury in the brain after ischemia/reperfusion.

Animals↗
PubMed2005

Vimentin-dependent spatial translocation of an activated MAP kinase in injured nerve.

How are phosphorylated kinases transported over long intracellular distances, such as in the case of axon to cell body signaling after nerve injury? Here, we show that the MAP kinases Erk1 and Erk2 are phosphorylated in sciatic nerve axoplasm upon nerve injury, concomitantly with the production of soluble forms of the intermediate filament vimentin by local translation and calpain cleavage in axoplasm. Vimentin binds phosphorylated Erks (pErk), thus linking pErk to the dynein retrograde motor via direct binding of vimentin to importin beta. Injury-induced Elk1 activation and neuronal regeneration are inhibited or delayed in dorsal root ganglion neurons from vimentin null mice, and in rats treated with a MEK inhibitor or with a peptide that prevents pErk-vimentin binding. Thus, soluble vimentin enables spatial translocation of pErk by importins and dynein in lesioned nerve.

Amino Acid Sequence↗
PubMed2006

The effect of single or repeated restraint stress on several signal molecules in paraventricular nucleus, arcuate nucleus and locus coeruleus.

The effect of single or repeated restraint stress on several signal molecules in the hypothalamus was studied in ICR mice. Single restraint stress was induced for 30, 60, and 120 min. A repeated restraint stress was induced for 2 h daily during four consecutive days, and then induced in the same time course on the fifth day. In the immunoblot assay, we observed that the signal molecules c-Fos, phosphorylated extracellular cell-regulated protein kinase (pERK), phosphorylated calcium/calmodulin dependent protein kinase II (pCaMKII) and phosphorylated cyclic-AMP response element binding protein (pCREB) in the hypothalamus were increased by single restraint, and the increased c-Fos and pERK levels were attenuated by repeated restraint stress. However, pCaMKII and pCREB levels were increased by both single and repeated restraint stress. We also observed in the immunohistochemistry study that immunoreactivities (IR) of these signal molecules were changed in paraventricular (PVN) and arcuate nuclei (ArcN) of the hypothalamus in accordance with immunoblot results. Furthermore, in confocal immunofluorescence, the pCaMKII and pCREB up-regulated by repeated restraint stress were co-localized within many neurons of PVN and ArcN. In addition, we found that c-Fos and pCaMKII IR in locus coeruleus (LC) were increased by single restraint, and were attenuated by repeated restraint stress. However, the pERK and pCREB IR were increased by both single and repeated restraint stress. The confocal study revealed that pERK and pCREB up-regulated by repeated restraint stress were co-localized within many neurons of LC. Our results suggest that single and repeated restraint stress differentially triggers the induction and phosphorylation of several signal molecules in the PVN, ArcN, and LC. In addition, single and repeated stress stimuli elicited the brain-region specific changes of signal molecules examined. Furthermore, the upstream signal molecule activating CREB may be also brain-region specific, especially in repeated stress stimuli.

Animals↗
PubMed2005

ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model.

Activation of extracellular signal-regulated kinase (ERK), a mitogen activated-protein kinase (MAPK), in dorsal horn neurons contributes to inflammatory pain by transcription-dependent and -independent means. We have now investigated if ERK is activated in the spinal cord after a spinal nerve ligation (SNL) and if this contributes to the neuropathic pain-like behavior generated in this model. An L5 SNL induces an immediate (<10 min) but transient (<6 h) induction of phosphoERK (pERK) restricted to neurons in the superficial dorsal horn. This is followed by a widespread induction of pERK in spinal microglia that peaks between 1 and 3 days post-surgery. On Day 10, pERK is expressed both in astrocytes and microglia, but by Day 21 predominantly in astrocytes in the dorsal horn. In the L5 DRG SNL transiently induces pERK in neurons at 10 min, and in satellite cells on Day 10 and 21. Intrathecal injection of the MEK (ERK kinase) inhibitor PD98059 on Day 2, 10 or 21 reduces SNL-induced mechanical allodynia. Our results suggest that ERK activation in the dorsal horn, as well as in the DRG, mediates pain through different mechanisms operating in different cells at different times. The sequential activation of ERK in dorsal horn microglia and then in astrocytes might reflect distinct roles for these two subtypes of glia in the temporal evolution of neuropathic pain.

Animals↗
PubMed2003

Intramolecular dephosphorylation of ERK by MKP3.

The dual specificity mitogen-activated protein kinase phosphatase MKP3 downregulates mitogenic signaling through dephosphorylation of extracellular signal-regulated kinase (ERK). Like other MKPs, MKP3 consists of a noncatalytic N-terminal domain and a catalytic C-terminal domain. ERK binding to the N-terminal noncatalytic domain of MKP3 has been shown to increase (up to 100-fold) the catalytic activity of MKP3 toward small artificial substrates. Here, we address the function of the N-terminal domain of MKP3 in either inter- or intramolecular dephosphorylation of pERK (phosphorylated ERK) and the stoichiometry of the MKP3/pERK Michaelis complex. These are important mechanistic distinctions given the observation that ERK exists in a monomer/dimer equilibrium that is shifted toward the dimer when phosphorylated and given that MKP3 undergoes catalytic activation toward other substrates when bound to ERK. Wild-type and engineered mutants of ERK and MKP3, binding analyses, reaction kinetics, and chemical cross-linking studies were used to demonstrate that the monomer of MKP3 binds to the monomeric form of pERK and that MKP3 within the resulting heterodimer performs intramolecular dephosphorylation of pERK. This study provides the first direct evidence that MKP3 utilizes intramolecular dephosphorylation between a complex consisting of one molecule each of MKP3 and ERK. Catalytic activation and substrate tethering by MKP3 lead to a >or=4000-fold rate enhancement (k(cat)/K(m)) for dephosphorylation of pERK.

Binding, Competitive↗
PubMed2006

Ribosomal stress couples the unfolded protein response to p53-dependent cell cycle arrest.

Protein misfolding in the endoplasmic reticulum (ER) triggers a signaling pathway termed the unfolded protein response path-way (UPR). UPR signaling is transduced through the transmembrane ER effectors PKR-like ER kinase (PERK), inositol requiring kinase-1 (IRE-1), and activating transcription factor 6 (ATF6). PERK activation triggers phosphorylation of eIF2alpha leading to repression of protein synthesis, thereby relieving ER protein load and directly inhibiting cyclin D1 translation thereby contributing to cell cycle arrest. However, PERK(-/-) murine embryonic fibroblasts have an attenuated G(1)/S arrest that is not attributable to cyclin D1 loss, suggesting a cyclin D1-independent mechanism. Here we show that the UPR triggers p53 accumulation and activation. UPR induction promotes enhanced interaction between the ribosome proteins (rpL5, rpL11, and rpL23) and Hdm2 in a PERK-dependent manner. Interaction with ribosomal proteins results in inhibition of Hdm2-mediated ubiquitination and degradation of p53. Our data demonstrate that ribosomal subunit:Hdm2 association couples the unfolded protein response to p53-dependent cell cycle arrest.

Cell Cycle↗
PubMed2004

Enhancement of stimulation-induced ERK activation in the spinal dorsal horn and gracile nucleus neurons in rats with peripheral nerve injury.

It has been suggested that low-threshold sensory pathways have an important role in the formation and maintenance of sensory abnormalities which are observed after peripheral nerve injury. In the present study, we examined the involvement of these pathways in the development of hyperexcitability after sciatic nerve injury (SNI) by detecting the intracellular signal molecule. The rats that received a transection of the sciatic nerve 7 days before were electrically stimulated at 0.1 mA and 3 mA in the proximal region of the nerve injury site. We found a small number of phosphorylated extracellular signal-regulated kinase (pERK)-labelled neurons in laminae I-II and III-IV of the spinal dorsal horn in the control rats after 0.1 mA stimulation. By contrast, there was a marked increased of pERK-labelled neurons both in the superficial laminae and laminae III-IV after the same stimulation in the SNI rats. Enhancement of ERK activation induced by 3 mA stimulation was also observed. Immunoreactivity of pERK in gracile nucleus neurons was also dramatically increased after 0.1 mA stimulation to the injured nerve. These data suggest that the rats with peripheral nerve injury had an increased responsiveness to the low- or high-threshold peripheral stimuli in I-II, III-IV and gracile nucleus neurons. Furthermore, SNI rats that received neonatal capsaicin treatment showed a decreased number of pERK neurons after 0.1 mA stimulation in the dorsal horn and gracile nucleus neurons compared to the control rats. Thus, C-fibres may contribute to the enhanced excitability of the low-threshold sensory neurons after peripheral nerve injury.

Animals↗
PubMed2006

The cellular protein P58IPK regulates influenza virus mRNA translation and replication through a PKR-mediated mechanism.

We previously hypothesized that efficient translation of influenza virus mRNA requires the recruitment of P58(IPK), the cellular inhibitor of PKR, an interferon-induced kinase that targets the eukaryotic translation initiation factor eIF2alpha. P58(IPK) also inhibits PERK, an eIF2alpha kinase that is localized in the endoplasmic reticulum (ER) and induced during ER stress. The ability of P58(IPK) to interact with and inhibit multiple eIF2alpha kinases suggests it is a critical regulator of both cellular and viral mRNA translation. In this study, we sought to definitively define the role of P58(IPK) during viral infection of mammalian cells. Using mouse embryo fibroblasts from P58(IPK-/-) mice, we demonstrated that the absence of P58(IPK) led to an increase in eIF2alpha phosphorylation and decreased influenza virus mRNA translation. The absence of P58(IPK) also resulted in decreased vesicular stomatitis virus replication but enhanced reovirus yields. In cells lacking the P58(IPK) target, PKR, the trends were reversed-eIF2alpha phosphorylation was decreased, and influenza virus mRNA translation was increased. Although P58(IPK) also inhibits PERK, the presence or absence of this kinase had little effect on influenza virus mRNA translation, despite reduced levels of eIF2alpha phosphorylation in cells lacking PERK. Finally, we showed that influenza virus protein synthesis and viral mRNA levels decrease in cells that express a constitutively active, nonphosphorylatable eIF2alpha. Taken together, our results support a model in which P58(IPK) regulates influenza virus mRNA translation and infection through a PKR-mediated mechanism which is independent of PERK.

Animals↗
PubMed2005

Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells.

Macrolide antibiotics decrease proinflammatory cytokine production in airway cells from subjects with chronic airway inflammation. However, in subjects with chronic obstructive pulmonary disease, short-term azithromycin (AZM) therapy causes a transient early increase in the blood neutrophil oxidative burst followed by a decrease in inflammatory markers with longer administration. We studied the effects of clarithromycin (CAM) and AZM on proinflammatory cytokine production from normal human bronchial epithelial (NHBE) cells. CAM decreased IL-8 over the first 6 h and then significantly increased interleukin (IL)-8 at 12-72 h after exposure (P < 0.0001). AZM also increased IL-8 at 24 and 48 h, and CAM increased granulocyte-macrophage colony-stimulating factor at 48 h. In the presence of LPS, both CAM and AZM dose-dependently increased IL-8 secretion over 24 h, but after 5 days of exposure to 10 microg/ml CAM there is suppression of IL-8 (P < 0.001). PD-98059, an inhibitor of MAP kinase/ERK kinase, inhibited CAM-induced IL-8 (P < 0.0001) and GM-CSF (P < 0.01) release. The p38 MAP kinase inhibitor SB-203580 increased CAM-induced IL-8 release (P < 0.001), and the c-jun NH2-terminal kinase inhibitor SP-600125 had no effect on IL-8. At 120 min and 6 h, CAM increased phospho-ERK1/2 (pERK) but not phospho-p38 or phospho-JNK. Over the first 90 min, CAM at 10 microg/ml inhibited pERK and then increased pERK in parallel with measured IL-8 secretion. After daily CAM exposure for 5 days, both IL-8 and pERK returned to baseline. The p38 MAP kinase inhibitor, SB-203580 increased ERK phosphorylation and IL-8 secretion. These results suggest that macrolide antibiotics can differentially modulate proinflammatory cytokine secretion in NHBE cells, in part through ERK.

Anti-Bacterial Agents↗
PubMed2005

Ontogeny of rapid estrogen-mediated extracellular signal-regulated kinase signaling in the rat cerebellar cortex: potent nongenomic agonist and endocrine disrupting activity of the xenoestrogen bisphenol A.

In addition to regulating estrogen receptor-dependent gene expression, 17beta-estradiol (E(2)) can directly influence intracellular signaling. In primary cultured cerebellar neurons, E(2) was previously shown to regulate growth and oncotic cell death via rapid stimulation of ERK1/2 signaling. Here we show that ERK1/2 signaling in the cerebellum of neonatal and mature rats was rapidly responsive to E(2) and during development to the environmental estrogen bisphenol A (BPA). In vivo dose-response analysis for each estrogenic compound was performed by brief (6-min) intracerebellar injection, followed by rapid fixation and phosphorylation-state-specific immunohistochemistry to quantitatively characterize changes in activated ERK1/2 (pERK) immunopositive cell numbers. Beginning on postnatal d 8, E(2) significantly influenced the number of pERK-positive cells in a cell-specific manner that was dependent on concentration and age but not sex. In cerebellar granule cells on postnatal d 10, E(2) or BPA increased pERK-positive cell numbers at low doses (10(-12) to 10(-10) M) and at higher (10(-7) to 10(-6) M) concentrations. Intermediate concentrations of either estrogenic compound did not modify basal ERK signaling. Rapid E(2)-induced increases in pERK immunoreactivity were specific to the ERK1/2 pathway as demonstrated by coinjection of the mitogen-activated, ERK-activating kinase (MEK)1/2 inhibitor U0126. Coadministration of BPA (10(-12) to 10(-10) M) with 10(-10) M E(2) dose-dependently inhibited rapid E(2)-induced ERK1/2 activation in developing cerebellar neurons. The ability of BPA to act as a highly potent E(2) mimetic and to also disrupt the rapid actions of E(2) at very low concentrations during cerebellar development highlights the potential low-dose impact of xenoestrogens on the developing brain.

Aging↗
PubMed2006

ER stress, hypoxia tolerance and tumor progression.

The development of chronic and fluctuating hypoxic regions in tumors has profound consequences for malignant progression, response to therapy and overall patient survival. Understanding the events involved in hypoxia tolerance will offer new opportunities for antitumor modalities. A universal response of tumor cells to hypoxia is a rapid and substantial decrease in the rates of macromolecular synthesis. Hypoxia induces phosphorylation of the translation initiation factor eIF2alpha on Ser51 via activation of the endoplasmic reticulum (ER) resident kinase PERK and that this modification is required for the rapid downregulation of global protein synthesis by this hypoxic stress. PERK-dependent phosphorylation of eIF2alpha is one component of the Unfolded Protein Response (UPR), a coordinated program that promotes cell survival under conditions of ER stress. Inactivation of PERK or eIF2alpha phosphorylation impairs cell survival under hypoxia, and transformed cells with inactivating PERK or eIF2alpha mutations form tumors in nude mice that are slower growing, and have higher levels of apoptosis in hypoxic areas compared to tumors with an intact UPR. Expression of the transcription factor ATF4, a downstream effector of eIF2alpha phosphorylation, is also upregulated by hypoxia in vitro and in human tumors and increases hypoxia tolerance. A second UPR pathway mediated by activation of IRE1 and its downstream target XBP1 is also required for hypoxia tolerance in vitro and for tumor growth. These results reveal a critical role for UPR activation for tumor cell resistance to hypoxia and tumor growth promotion and suggest that the UPR may be an attractive target for anti-tumor modalities.

Animals↗
PubMedDate not supplied

Perquisites: the intrinsic form of pay.

Compensation packages, particularly for executives, are made up of five elements--salary, employee benefits, short-term incentives, long-term incentives, and perquisites. Of these, perquisites are probably the most misunderstood, according to author Bruce Ellig, vice-president of Corporate Compensation and Benefits for Pfizer Inc. The value of perquisites, or "perks," is their degree of exclusivity--that is, their worth as status symbols or "membership benefits" for those employees at or above a certain level in the company's hierarchy. And their value is enhanced when they (as some do) qualify for favorable tax treatment. True perks fall into six categories--time off with pay, executive services, nonperformance awards, health-care, survivor protection, and retirement coverage. Within these categories, perks take many forms. Time off with pay, for example, might include employment contracts, liberalized vacations, the privilege of working at home, disability benefits, sabbaticals, severance pay, or outplacement assistance. The use of perks varies among companies, but is more popular among small companies.

Health Benefit Plans, Employee↗
PubMed2006

BLIMP-1 is a target of cellular stress and downstream of the unfolded protein response.

B lymphocyte-induced maturation protein-1 (BLIMP-1) acts during differentiation of B cells and monocytes, but was originally identified as a repressor of the IFN-beta promoter induced during viral infection. A central regulator of the intracellular response to viral infection is the interferon-inducible double-stranded RNA activated protein kinase (PKR). PKR belongs to a family of kinases that phosphorylate the eukaryotic translation initiation factor 2-alpha (eIF2alpha) and activate common downstream signaling pathways. PERK, the endoplasmic reticulum resident PKR-homologue, is activated during the unfolded protein response (UPR), a stress response involved in both macrophage activation and terminal B-cell differentiation. This suggested that BLIMP-1 might be a target of stress responses involving PERK. We demonstrate that BLIMP-1 is rapidly up-regulated during the UPR in human myeloid and B-cell lines. This response is conserved in murine B-cells and murine macrophages, in which mimics of physiological stress and classical activation stimuli also induce Blimp-1. During the UPR, BLIMP-1 mRNA is induced at the level of transcription. This response is dependent on an intact PERK signaling pathway, independent of new protein synthesis and blocked by an inhibitor of NF-kappaB. Our data provide evidence for a novel pathway linking cellular stress to BLIMP-1, a regulator of differentiation in macrophages and B cells.

Animals↗
PubMed2005

Distinct endoplasmic reticulum stress responses are triggered during human liver transplantation.

Injury due to cold ischaemia-reperfusion (IR) represents a major cause of primary graft non-function following human liver transplantation. This major cellular response translates into a dramatic decrease in intracellular ATP concentration during the ischaemic phase, thus sensitizing cells to reperfusion shock. We postulated that IR-induced cellular damage might cause alterations of the secretory pathway, particularly at the level of endoplasmic reticulum (ER) function. Under these circumstances, the ER triggers an adaptive response named the 'unfolded protein response' (UPR). In this study, we show that the expression of BiP, CHOP/GADD153 and GADD34, known to be induced specifically upon ER stress, are differentially affected upon IR, thus suggesting that distinct ER stress responses are activated during each phase of transplantation. With an approach combining semi-quantitative RT-PCR and immunoblotting using phospho-specific antibodies, we show that the IRE-1 pathway is activated upon early ischaemia and, in a second phase, upon early reperfusion. This occurs through the atypical splicing of XBP-1 mRNA, its translation into a transcriptionally active XBP-1 protein and the subsequent increase in EDEM mRNA expression, and may also contribute to the observed reperfusion-induced activation of MAPK/SAPK. In contrast, we demonstrate that the PERK pathway, leading to inhibition of cap-dependent translation, is mainly activated upon reperfusion, as shown by PERK and eIF2alpha phosphorylation. PERK activation is detected restrictively in sinusoidal endothelial cells and could contribute to the exaggerated sensivity of this liver cell type to IR injury. These results correlate well with the observed defect in protein secretion and suggest that the biphasic ER stress response may influence liver secretory functions and, as a consequence, condition liver transplantation outcomes.

Endoplasmic Reticulum↗