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Biochemical Pharmacology (v.72, #11)

Editorial Advisory Board (pp. iii).

Interaction between the insulin receptor and Grb14: A dynamic study in living cells using BRET by Sébastien Nouaille; Christophe Blanquart; Vladimir Zilberfarb; Nicolas Boute; Dominique Perdereau; Anne-Françoise Burnol; Tarik Issad (pp. 1355-1366).

Grb14 is a molecular adaptor that binds to the activated insulin receptor (IR) and negatively regulates insulin signaling. We have studied the dynamics of interaction of the IR with Grb14, in real time, in living HEK cells, using bioluminescence resonance energy transfer (BRET). Insulin rapidly and dose-dependently stimulated this interaction. Removing insulin from the incubation medium only resulted in a modest decrease in BRET signal, indicating that the interaction between the IR and Grb14 can remain long after insulin stimulus has disappeared. BRET saturation experiments indicated that insulin markedly increases the affinity between IR and Grb14, resulting in recruitment of the adaptor to the activated IR. In addition, using both BRET and co-immunoprecipitation experiments, we demonstrated that insulin induced the dimerization of Grb14, most likely as a result of simultaneous binding of two Grb14 molecules on the activated IR. We also investigated the relationships between IR, Grb14 and the protein tyrosine phosphatase PTP1B. We observed that insulin-induced BRET between the IR and PTP1B was markedly reduced by Grb14, suggesting that Grb14 regulated this interaction in living cells. Using site-specific antibodies against phosphorylated tyrosines of the insulin receptor, we showed that Grb14 protected the three tyrosines of the kinase loop from dephosphorylation by PTP1B, while favouring dephosphorylation of tyrosine 972. This resulted in decreased IRS-1 binding to the IR and decreased activation of the ERK pathway. Our work suggests that Grb14 may regulate signalling through the insulin receptor by controlling its tyrosine-dephosphorylation in a site-specific manner.

Keywords: Abbreviations; IR; insulin receptor; Grb; growth factor receptor binding; TK; tyrosine kinase; PTP1B; protein tyrosine phosphatase 1B; IRS-1; insulin receptor subtrate 1; Shc; Src homology collagen; MAP kinases; mitogen activated protein kinases; ERK; extracellular signal-regulated kinases; PI3-kinase; phosphoatidyl inositol 3-kinase; PH; pleckstrin homology; SH2; Src homology 2; BPS/PIR; (between PH and SH2/phosphorylated insulin receptor interacting region); Rluc; Renilla; luciferase; YFP; yellow fluorescent protein; BRET; bioluminescence resonance energy transfer; mBU; milliBRET unit; PTPα/ɛ; protein tyrosine phosphatase α/ɛ; IGF-1; insulin-like growth factor-1; WGL; wheat germ lectinBRET; Insulin receptor; Grb14; PTP1B; IRS-1; MAP kinases

Listeria monocytogenes induced Rac1-dependent signal transduction in endothelial cells by Bernd Schmeck; Wiebke Beermann; Vincent van Laak; Bastian Opitz; Andreas C. Hocke; Karolin Meixenberger; Julia Eitel; Trinad Chakraborty; Gudula Schmidt; Holger Barth; Norbert Suttorp; Stefan Hippenstiel (pp. 1367-1374).

Infection of endothelial cells by Listeria monocytogenes is an essential step in the pathogenesis of listeriosis. Small GTPases of the Rho family act as molecular switches in signal transduction. We tested the hypothesis that Rho GTPases contribute to the regulation of cytokine expression following L. monocytogenes infection. L. monocytogenes induced release of distinct CC and CXC, as well as Th1 and Th2 cytokines and growth factors by endothelial cells and activated RhoA and Rac1. Inhibition of Rac1 by inhibitor Nsc23766 reduced cytokine expression, and slightly yet significantly the uptake of bacteria. Blocking of Rho proteins by Clostridium difficile toxin B-10463 (TcdB) reduced Listeria-dependent cytokine expression, whereas activating Rho proteins by Escherichia coli CNF1 increased it. We analyzed regulation of IL-8 expression in more detail: Listeria-induced IL-8 release was reduced by inhibition of RhoA, Rac1 and Cdc42 (TcdB) or Rac1 while blocking of RhoA/B/C by Clostridium limosum C3 fusion toxin (C3FT) or Rho kinase by Y27632 reduced cytokine expression only slightly. Activation of RhoA, Rac1 and Cdc42 (CNF1), but not of RhoA alone (CNF_Y), enhanced Listeria-dependent IL-8 release significantly. Furthermore, inhibition of RhoA, Rac1 and Cdc42 (TcdB) and Rac1 (Nsc23766), but not of RhoA (C3FT) reduced Listeria-related recruitment of NF-κB/p65 and RNA polymerase II to the il8 promoter, as well as acetylation of histone H4 and Ser10/Lys14-phosphorylation/acetylation of histone H3 at the il8 gene promoter in HUVEC.In conclusion, Rac1 contributed to L. monocytogenes-induced cytokine expression by human endothelial cells.

Keywords: Rac1; Listeria; Histones; Endothelial cells; Bacterial toxins; Cytokines

Multiple role of histamine H₁-receptor–PKC–MAPK signalling pathway in histamine-stimulated nerve growth factor synthesis and secretion by Metoda Lipnik-Stangelj (pp. 1375-1381).

Histamine is a potent stimulator of nerve growth factor (NGF) production in the central nerve system and in the periphery as well. In this review, the biochemical mechanisms of histamine-stimulated NGF synthesis and secretion, and interactions between histamine, interleukin-1beta, and interleukin-6 are discussed. The main signalling pathway, involved in the stimulation of NGF production by histamine, includes activation of histamine H₁-receptor, stimulation of Ca²⁺-dependent protein kinase C and mitogen-activated protein kinase. The same signalling pathway is involved in the interactions between histamine, interleukin-1beta, and interleukin-6, where NGF secretion is amplified. Whereas histamine and interleukin-1beta cause additive stimulatory effect on NGF secretion, interaction between histamine and interleukin-6 causes a long-term synergism.Thus, activation of histamine H₁-receptor–protein kinase C–mitogen-activated protein kinase signalling pathway plays a crucial role not only in the direct stimulation of NGF secretion by histamine, but also in the indirect stimulation via different types of interactions between histamine, interleukin-1beta, and interleukin-6, which may have important therapeutic implications in modulation of NGF production.

Keywords: Abbreviations; AP-1; activator protein-1; CNS; central nerve system; ERK; extra-cellular signal-regulated kinase; IL; interleukin; JAK; Janus kinases; JNK; JUN-N-terminal kinase; MAPK; mitogen-activated protein kinase; MEK1; MAPK kinase 1; NGF; nerve growth factor; PI3; -3 kinase; PKC; protein kinase C; TPA; 12-; O; -tetradecanoylphorbol-13-acetate; TRE; TPA-response element; TrkA; tropomyosin-receptor kinase A; STAT; signal transducers and activators of transcriptionHistamine; Interleukin; Histamine H; ₁; -receptor; PKC; MAPK; NGF

Igf-I extends the chondrogenic potential of human articular chondrocytes in vitro: Molecular association between Sox9 and Erk1/2 by Mehdi Shakibaei; Claudia Seifarth; Thilo John; Masyar Rahmanzadeh; Ali Mobasheri (pp. 1382-1395).

Expansion of articular chondrocytes in monolayer culture leads to loss of the unique chondrocyte phenotype and the cells’ redifferentiation capacity. Dedifferentiation of chondrocytes in monolayer culture is a challenging problem for autologous chondrocyte transplantation (ACT). It is well established that Igf-I exerts positive anabolic effects on chondrocytes in vivo and in vitro. Accordingly, in this study, we examined whether the anabolic insulin-like growth factor-I (Igf-I) is capable of extending the chondrogenic potential of dedifferentiated chondrocytes in vitro. Chondrocyte monolayers were cultured up to 10 passages. At each passage chondrocytes were stimulated with Igf-I (10ng/ml) and introduced to high-density cultures for up to 7 days. Expression of collagen type II, cartilage-specific proteoglycans, activated caspase-3, integrin β1, extracellular signal-regulated kinase (Erk) and Sox9 was examined by Western blotting, immunoprecipitation and immunomorphological techniques. Monolayer chondrocytes rapidly lost their differentiated phenotype. When introduced to high-density cultures, only chondrocytes from P1–P4 redifferentiated. In contrast, Igf-I treated cells from P1 up to P7 redifferentiated and formed cartilage-like tissue in high-density culture. P8–P10 cells exhibited apoptotic alterations and produced significantly less matrix. Igf-I markedly increased expression of integrin β1, Erk and Sox9 . Immunoprecipitation revealed that phosphorylated Erk1/2 physically interacts with Sox9 in chondrocyte nuclei, suggesting a previously unreported functional association which was markedly enhanced by Igf-I. Treatment of chondrocyte cultures with Igf-I stabilizes chondrogenic potential, stimulates Sox9 and promotes molecular interactions between Erk and Sox9. These effects appear to be regulated by the integrin/MAPK signaling pathways.

Keywords: Chondrocyte; Igf-I; Apoptosis; Sox9; Erk1/2; High-density culture; Immunoprecipitation

Enrichment of non-synchronized cells in the G1, S and G2 phases of the cell cycle for the study of apoptosis by Arnaud Coquelle; Shahul Mouhamad; Marie O. Pequignot; Thorsten Braun; Gabrielle Carvalho; Sonia Vivet; Didier Métivier; Maria Castedo; Guido Kroemer (pp. 1396-1404).

The susceptibility of cells to apoptosis induction is deeply influenced by their position in the cell cycle. Unfortunately, however, current methods for the enrichment of cells in defined phases of the cell cycle are mostly based on the synchronization of cells by agents or conditions that are intrinsically toxic and induce apoptosis on their own. We developed a novel procedure for the purification of cells in distinct phases of the cell cycle. This method is based on the stable transfection of cells with a chimeric protein made up by histone H2B and green fluorescent protein (GFP). Cytofluorometric purification of cells defined by their size and their H2B-GFP-dependent fluorescence (which reflects chromatin and hence DNA content) allowed for the efficient separation of diploid and tetraploid cells in the fluorescence-activated cell sorter (FACS). Moreover, when applied to diploid cells, this method allowed for the enrichment of live, functional cells in the G1, S and G2 phases of the cell cycle. FACS-purified cells were viable and readily resumed the cell cycle upon reculture. While staurosporine was equally toxic for cells in any phase of the cell cycle, camptothecin was particularly toxic for cells in the S phase. Moreover, BAY11-7082, a specific inhibitor of the IKK complex required for NF-κB activation, exhibited a particular cell cycle-specific profile of toxicity (G2>S>G1). These results delineate a novel procedure for studying the intersection between cell cycle regulation and cell death mechanisms.

Keywords: Abbreviations; BrdU; 5-bromo-2-deoxyuridine; Casp-3a; activated caspase-3; FACS; fluorescence-activated cell sorter; GFP; green fluorescent protein; H2B; histone H2B; H3P; phosphorylated histone H3; PI; propidium iodide; STS; staurosporineCell sorting; Ploidy; Cell death; Chemoresistance; IKK

Different fates of intracellular glutathione determine different modalities of apoptotic nuclear vesiculation by Milena De Nicola; Giampiero Gualandi; Alberto Alfonsi; Claudia Cerella; Maria D’Alessio; Antonio Bergamaschi; Andrea Magrini; Lina Ghibelli (pp. 1405-1416).

U937 monocytic cells show two main apoptotic nuclear morphologies, budding and cleavage, that are the result of two independent morphological routes, since they never interconvert one into the other, and are differently modulated by stressing or physiological apoptogenic agents [Exp Cell Res 1996; 223:340–347]. With the aim of understanding which biochemical alterations are at the basis of these alternative apoptotic morphologies, we performed an in situ analysis that showed that in U937 cells intracellular glutathione (GSH) is lost in cells undergoing apoptosis by cleavage, whereas it is maintained in apoptotic budding cells. Lymphoma cells BL41 lose GSH in apoptosis, and show the cleavage nuclear morphology; the same cells latently infected with Epstein Barr Virus (E2r line) undergo apoptosis without GSH depletion and show the budding nuclear morphology. GSH depletion is not only concomitant to, but is the determinant of the cleavage route, since the inhibition of apoptotic GSH efflux with cystathionine or methionine shifts the apoptotic morphology from cleavage to budding. Accordingly, cystathionine or methionine antagonizes apoptosis in the all-cleavage BL41, without affecting the all-budding E2r.

Keywords: Apoptosis; Nuclear morphologies; Budding; Cleavage; In situ; glutathione measurement; Epstein Barr Virus

p63 and p73, members of the p53 gene family, transactivate PKCδ by Raffaella Ponassi; Alessandro Terrinoni; Anissa Chikh; Alessandro Rufini; Anna Maria Lena; Berna S. Sayan; Gerry Melino; Eleonora Candi (pp. 1417-1422).

The p53 family comprises three genes that encode for p53, p63 and p73. These genes have a significant degree of sequence homology, especially in the central sequence-specific DNA-binding domain. The high homology among the three DNA-binding domains indicates that these transcription factors have identical residues interacting with DNA, and thus potentially can recognize the same transcriptional targets. In this study, we demonstrate that PKCδ is induced by p63 and p73 in Saos2 cells. The putative human PKCδ promoter harbours three p53-like binding sites (RE I, RE II, RE III). In order to confirm the transactivation of PKCδ by p53 family members, we performed transcription assays using the entire or selected regions of the promoter upstream of a luciferase reporter gene. The results obtained demonstrated that, at least in vitro, the p53 family members tested (TAp63α, TAp73α, ΔNp63α, but not ΔNp73α) were able to drive transcription from the PKCδ promoter.

Keywords: Abbreviations; PKC; protein kinase C; TA; transactivation domain; ΔN; amino terminal truncated protein; Dox; doxycycline; BSA; bovine serum albumin; RE; responsive element; NHEK; normal human epidermal keratinocytesp53 family members; Epidermis; Keratinocytes; Skin; PKCδ; Differentiation

The immunomodulator AS101 induces growth arrest and apoptosis in Multiple Myeloma: Association with the Akt/Survivin pathway by Michal Hayun; Yaniv Naor; Merav Weil; Michael Albeck; Alpha Peled; Jeremy Don; Nechama Haran-Ghera; Benjamin Sredni (pp. 1423-1431).

Multiple Myeloma (MM) is a clonal B-cell malignancy affecting both the immune and the skeletal systems, and accounts for 10% of all hematological cancers. The immunomodulator ammonium trichloro (dioxoethylene-O,O′) tellurate (AS101) is a non-toxic compound which has direct anti-tumoral properties in several tumor models. The present study examined the anti-tumoral activity of AS101 in MM by targeting the Akt/Survivin signaling pathway, crucial for survival. We showed that AS101 inhibites cell proliferation and colonies formation of MM cell lines, in a dose-dependent manner. AS101 induced G₂/M growth arrest and increased both cyclin-dependent kinase inhibitor p21^waf1 protein levels and Cdk1 (p34^cdc2)—inhibitory phosphorylation. Longer incubation of MM cells with AS101 resulted in accumulation of apoptotic cell population and in increased caspase 9, 3 and 7 activities. We also showed that AS101 down-regulated Akt phosphorylation and decreased expression of the inhibitor of apoptosis, survivin. Since Akt and survivin are potentials targets for MM therapy, we suggest that AS101, currently being used in clinical studies, may have therapeutic implications in myeloma and other hematopoietic malignancies.

Keywords: JEL classification; Inflammation; ImmunopharmacologyAbbreviations; Cdk; cyclin-dependent kinase; IAPs; inhibitors of apoptosis proteins; IGF-1; insulin-like growth factor 1; MM; Multiple Myeloma; PI; propidium iodide; PI3-K; phosphatidylinositol-3-OH kinaseAS101; Multiple Myeloma; Survivin; Akt; Apoptosis; Caspases

Alkylating drugs applied in non-cytotoxic doses as a novel compounds targeting inflammatory signal pathway by A. Pukhalsky; G. Shmarina; V. Alioshkin; A. Sabelnikov (pp. 1432-1438).

Alkylating drugs (ADs) belonging to the nitrogen mustard family are commonly used as cytostatic and immunosuppressive agents. Our previous in vitro studies demonstrated that in the case of gradual dose decrease, the number of targets for alkylation in the cell is also reduced and the drug switches from brutal cytostatic to cell growth modifier. At doses of 0.3μg/ml and lower, the effects of ADs are no longer associated with DNA damage or stress/MAPK pathways activation. Instead, the disruption of signal transduction by the IL-2β and/or TNFα cell surface receptors is observed. As a result, ADs in the doses 100-fold lower than cytostatic ones are capable to modify lymphocyte activity including the activity of regulatory T cells. We hypothesized that ADs may have a beneficial effect in the treatment of inflammatory diseases. Indeed, the application of non-cytotoxic doses of an AD melphalan reduces the severity of murine experimental colitis. Daily administration of melphalan (25μg/kg body weight) markedly reduced the severity of DSS-colitis as determined by clinical and histological criteria. Moreover, the beneficial effect of melphalan was also shown in asthmatic patients. In 60% of these patients histological and ultrastructural signs of bronchial epithelium regeneration were also revealed. Thus, ADs at non-cytotoxic concentrations exert beneficial effect both in acute and chronic inflammatory diseases. Such anti-inflammatory activity is thought to be due to blocking of signal transduction through various cell surface receptor including IL-2R and TNFR. Consequently different steps of inflammatory cascade turn out to be inhibited.

Keywords: Alkylating drugs; Regulatory T cell; IL-2 receptor; TNF receptor; NFκB; Experimental colitis

Regulation of inflammation and redox signaling by dietary polyphenols by Irfan Rahman; Saibal K. Biswas; Paul A. Kirkham (pp. 1439-1452).

Reactive oxygen species (ROS) play a key role in enhancing the inflammation through the activation of NF-κB and AP-1 transcription factors, and nuclear histone acetylation and deacetylation in various inflammatory diseases. Such undesired effects of oxidative stress have been found to be controlled by the antioxidant and/or anti-inflammatory effects of dietary polyphenols such as curcumin (diferuloylmethane, a principal component of tumeric) and resveratrol (a flavanoid found in red wine). The phenolic compounds in fruits, vegetables, tea and wine are mostly derivatives, and/or isomers of flavones, isoflavones, flavonols, catechins, tocopherols, and phenolic acids. Polyphenols modulate important cellular signaling processes such as cellular growth, differentiation and host of other cellular features. In addition, they modulate NF-κB activation, chromatin structure, glutathione biosynthesis, nuclear redox factor (Nrf2) activation, scavenge effect of ROS directly or via glutathione peroxidase activity and as a consequence regulate inflammatory genes in macrophages and lung epithelial cells. However, recent data suggest that dietary polyphenols can work as modifiers of signal transduction pathways to elicit their beneficial effects. The effects of polyphenols however, have been reported to be more pronounced in vitro using high concentrations which are not physiological in vivo. This commentary discusses the recent data on dietary polyphenols in the control of signaling and inflammation particularly during oxidative stress, their metabolism and bioavailability.

Keywords: Abbreviations; AP-1; activator protein 1; ARE; antioxidant response elements; ATF1; activating transcription factor; CAPE; caffeic acid phenethyl ester; COPD; chronic obstructive pulmonary disease; COX-2; cyclooxygenase-2; CRE; cyclic AMP response element; CREB; CRE-binding protein; EC; (2)-epicatechin; EGC; epicatechin gallate; EGCG; epigallocatechin gallate; EGFR; early growth response; ELAM-1; endothelial leukocyte adhesion molecule 1; EpRE; electrophilic response element; ERK; extracellular signal-regulated kinase; FEV; ₁; forced expiratory volume in 1; s; GCLC; glutamate-cysteine ligase catalytic subunit; G-CSF; colony-stimulating factor 3; GM-CSF; colony-stimulating factor 2; GSH; reduced glutathione; H; ₂; O; ₂; hydrogen peroxide; HAT; histone acetyltransferase; HDAC; histone deacetylase; HDAC2; histone deacetylase-2; HO-1; heme oxygenase-1; ICAM-1; intercellular adhesion molecule-1; IFN-γ; gamma interferon; IK; I-kappa kinase; IL-1α; interleukin 1 α; IL-1β; interleukin 1 β; IL-6; interleukin 6; iNOS; inducible nitric oxide synthase; IRAK; IL-1β receptor-associated kinase; IRF-1; IFN regulatory factor; IκBα; inhibitory kappa B; JNK; c-Jun N-terminal kinases; LPS; lipopolysaccharide; MAPK; mitogen activated protein kinase; MAPKK; mitogen-activated protein kinase kinase; MCP-1; monocyte chemotactic peptide-1; M-CSF; colony-stimulating factor 1; MEK; mitogen-activated kinase; MMP-9; matrix metallo proteinases; MSK-1; mitogen and stress-activated protein kinase-1; NF-E2; nuclear factor erythroid derived 2; NF-κB; nuclear factor-kappa B; NIK; NF-κB inducing kinase; NO; nitric oxide; Nrf2; nuclear redox factor; O; ₂; ⁻; superoxide anion; PUFA; polyunsaturated fatty acids; RANTES; regulated on activation; normal T cell expressed and secreted; ROS; reactive oxygen species; SOD; superoxide dismutase; TGF-beta; transforming growth factor beta; TNF; tumor necrotic factor; TRAIL; tumor necrosis factor related apoptosis-inducing ligand; VCAM-1; vascular cell adhesion molecule-1; VEGF; vascular endothelial growth factorCurcumin; Resveratrol; Oxidants; Glucocorticoids; Histone deacetylase; NF-κB; Nrf2

Unscrambling the role of human parvovirus B19 signaling in systemic autoimmunity by Gregory J. Tsay; Moncef Zouali (pp. 1453-1459).

Despite enormous progress in understanding how the immune system works, the pathogenesis of autoimmune diseases still remains unclear. Growing evidence indicates that infectious agents can be potent initial triggers, subverting and exploiting host cell signaling pathways. This role is exemplified by the association of parvovirus B19 (B19) with human autoimmune disease. Infection with this common virus exhibits striking similarities with systemic autoimmune diseases, and can be associated with elevated serum autoantibody titers. The B19 virus produces proline-rich, 11-kDa proteins that have been implicated in modulation of host signaling cascades involved in virulence and pathogenesis. Additionally, B19 produces a non-structural protein (NS1) that functions as a transcription regulator by directly binding the p6 promoter and the Sp1/Sp3 transcription factors. The protein is also involved in DNA replication, cell cycle arrest and initiation of apoptotic damage, particularly in erythroid cells. When transfected to non-permissive cells, NS1 recruits the mitochondria cell death pathway. It is even more remarkable that NS1 functions as a trans-acting transcription activator for the IL6 promoter, up-regulating IL6 expression in host cells. Hence, B19 infection may play a pivotal role in triggering inflammatory disorders. By promoting apoptotic damage and trans-activating pro-inflammatory cytokine promoters, B19 may break the delicate balance between cell survival and apoptosis, and may contribute to immune deregulation. Understanding the mechanisms used by B19 to alter the cell signaling machinery may provide further insight into the mechanism by which autoimmune diseases develop.

Keywords: Abbreviations; ANCA; antibody to neutrophil cytoplasmic antigens; β2GPI; β2 glycoprotein I; CL; cardiolipin; B19; parvovirus B19Rheumatoid arthritis; Lupus; Human parvovirus B19; Signaling; Immune subversion; Autoimmunity

New approaches to blockade of α4-integrins, proven therapeutic targets in chronic inflammation by Christiane Kummer; Mark H. Ginsberg (pp. 1460-1468).

The recruitment of leukocytes into tissue is a pivotal step in inflammation. α4-Integrins are adhesion receptors on circulating leukocytes that mediate attachment to the endothelium and facilitate their migration into the inflamed tissue. This multistep process is mediated by the interaction of α4-integrins with their counter receptors VCAM-1 and MadCAM-1 that are expressed on endothelial cells. α4-Integrins act as both adhesive and signaling receptors. Paxillin, a signaling adaptor molecule, binds directly to the α4 cytoplasmic tail and its binding is important for cell migration. Blocking the adhesive functions of α4-integrins has been shown to be an effective therapeutic approach in the treatment of autoimmune diseases, but also carries the risk of defects in development, hematopoiesis and immune surveillance. Interfering with α4 signaling by inhibiting the α4–paxillin interaction decreases α4-mediated cell migration and adhesion to VCAM-1 and MadCAM under shear flow. These in vitro effects are accompanied by a selective impairment of leukocyte migration into inflammatory sites when the α4–paxillin interaction is blocked in vivo. Thus, blockade of α4-integrin signaling may offer a novel strategy for interfering with the functions of these receptors in pathological events while sparing important physiological functions.

Keywords: Integrins; Chronic inflammation; Therapeutic targets; Cell migration

Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages by Mayra Solis; Delphine Goubau; Raphaëlle Romieu-Mourez; Pierre Genin; Ahmet Civas; John Hiscott (pp. 1469-1476).

Type I IFN (IFN-α/β) have important biological functions ranging from immune cell development and activation, to tumor cell killing and most importantly inhibition of virus replication. Following viral infection or activation of Toll-like receptors (TLRs) via distinct ligands, IFN-α/β are produced. Two members of the interferon regulatory factor (IRF) family – IRF-3 and IRF-7 – are the major modulators of IFN gene expression. Activation of IRF-3 and IRF-7 by TBK1/IKKɛ mediated phosphorylation promotes IFN gene expression and potentiates the production of IFN responsive genes important to the development of an effective antiviral immune response. IFN treatment can augment anti-tumor properties and they are potentially key players in cancer therapy. For example, adoptive transfer of IFN-γ-activated macrophages can mediate tumor cell killing via direct cell–cell contact, as well as release of soluble cytotoxic pro-inflammatory molecules. A recent study investigated whether IRF-3 and IRF-7 could mediate the acquisition of new anti-tumor effector functions in macrophages. Adenovirus mediated transduction of the active form of IRF-7 into primary macrophages resulted in the production of type I IFN, upregulation of target genes including TRAIL and increased tumoricidal activity of macrophages; in contrast, the active form of IRF-3 led to induction of cell death. These studies indicate that IRF-7 transduced macrophages may be an attractive candidate for in vivo adoptive therapy of cancer.

Keywords: Macrophages; IRF-3; IRF-7; Type I IFN; Anti-tumor activity

Recruitment of an interferon molecular signaling complex to the mitochondrial membrane: Disruption by hepatitis C virus NS3-4A protease by John Hiscott; Judith Lacoste; Rongtuan Lin (pp. 1477-1484).

Recent advances in the understanding of the signaling pathways leading to the host antiviral response to hepatitis C virus (HCV), the mechanisms used by HCV to evade the immune response, and the development of small molecule inhibitors of HCV have generated optimism that novel therapeutic approaches to control HCV disease may soon be available. HCV infection is detected by the cytoplasmic, RNA helicase RIG-I that plays an essential role in signaling to the host antiviral response. Recently the adapter molecule that links RIG-I sensing of incoming viral RNA to downstream signaling and gene activation events was characterized by four different groups: MAVS/IPS-1-1/VISA/Cardif contains an amino-terminal CARD domain and carboxyl-terminal mitochondrial transmembrane sequence that localizes to the mitochondrial membrane. Furthermore, the hepatitis C virus NS3-4A protease complex specifically targets MAVS/IPS-1/VISA/Cardif for cleavage as part of its immune evasion strategy. Using a combination of biochemical analysis, subcellular fractionation and confocal microscopy, we demonstrate that: (1) NS3-4A cleavage of MAVS/IPS-1/VISA/Cardif causes relocation from the mitochondrial membrane to the cytosolic fraction, resulting in disruption of signaling to the antiviral immune response; (2) disruption requires a function NS3-4A protease; (3) a point mutant of MAVS/IPS-1/VISA/Cardif (Cys508Ala) is not cleaved from the mitochondria by active protease; and (4) the virus-induced IKKɛ kinase, but not TBK1, co-localizes strongly with MAVS at the mitochondrial membrane and the localization of both molecules is disrupted by NS3-4A expression. These observations provide an outline of the mechanism by which HCV evades the IFN antiviral response.

Keywords: Hepatitis C; Interferon; RIG-I; Viral evasion; IRF

Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1 by Joshua T. Dilworth; Janice M. Kraniak; Jonathan W. Wojtkowiak; Richard A. Gibbs; Richard F. Borch; Michael A. Tainsky; John J. Reiners Jr.; Raymond R. Mattingly (pp. 1485-1492).

Neurofibromatosis type 1 (NF1) is the most common cancer predisposition syndrome. NF1 patients present with a constellation of clinical manifestations and have an increased risk of developing certain benign and malignant tumors. This disease results from mutation within the gene encoding neurofibromin, a GTPase activating protein (GAP) for Ras. Functional loss of this protein compromises Ras inactivation, which leads to the aberrant growth and proliferation of neural crest-derived cells and, ultimately, tumor formation. Current management of NF1-associated malignancy involves radiation, surgical excision, and cytotoxic drugs. The limited success of these strategies has fueled researchers to further elucidate the molecular changes that drive tumor formation and progression. This discussion will highlight how intracellular signaling molecules, cell-surface receptors, and the tumor microenvironment constitute potential therapeutic targets, which may be relevant not only to NF1-related malignancy but also to other human cancers.

Keywords: Abbreviations; EGFR; epidermal growth factor receptor; FTI; farnesyl transferase inhibitor; GGTI; geranylgeranyl transferase inhibitor; GAP; GTPase activating protein; MPNST; malignant peripheral nerve sheath tumor; NF1; type 1 neurofibromatosis; PAK; p21-activated kinase; PAT; protein fatty acyltransferaseNeurofibromin; Ras; Statin; Prenylation; MAP kinase; EGF receptor

NF-κB activation by reactive oxygen species: Fifteen years later by Geoffrey Gloire; Sylvie Legrand-Poels; Jacques Piette (pp. 1493-1505).

The transcription factor NF-κB plays a major role in coordinating innate and adaptative immunity, cellular proliferation, apoptosis and development. Since the discovery in 1991 that NF-κB may be activated by H₂O₂, several laboratories have put a considerable effort into dissecting the molecular mechanisms underlying this activation. Whereas early studies revealed an atypical mechanism of activation, leading to IκBα Y42 phosphorylation independently of IκB kinase (IKK), recent findings suggest that H₂O₂ activates NF-κB mainly through the classical IKK-dependent pathway. The molecular mechanisms leading to IKK activation are, however, cell-type specific and will be presented here. In this review, we also describe the effect of other ROS (HOCl and¹O₂) and reactive nitrogen species on NF-κB activation. Finally, we critically review the recent data highlighting the role of ROS in NF-κB activation by proinflammatory cytokines (TNF-α and IL-1β) and lipopolysaccharide (LPS), two major components of innate immunity.

Keywords: Abbreviations; Abl; abelson murine leukemia viral; ASK1; apoptosis signal-regulating kinase1; BHA; butylated hydroxyanisole; DMSO; dimethylsulfoxide; GSH; reduced gluthation; JNK; c-Jun N-terminal kinase; MyD88; myeloid differentiation marker 88; NAC; N; -acetyl-cysteine; PEST; proline, glutamate, serine, threonine; p56Lck; lymphocyte specific tyrosine kinase; PDTC; pyrrolidine-9-dithiocarbamate; PKD; protein kinase D; PKCδ; protein kinase Cδ; ROS; reactive oxygen species; SOD; superoxide dismutase; Syk; spleen tyrosine kinase; SHIP-1; SH2-containing inositol 5-phosphatase 1; TAK1; transforming growth factor-β-activated kinase; ZAP70; zeta-chain (TCR) associated protein kinaseNF-κB; Reactive oxygen species; Cellular signalling; Cytokines; LPS

Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skin in vivo: NF-κB and AP-1 as prime targets by Joydeb Kumar Kundu; Young Kee Shin; Young-Joon Surh (pp. 1506-1515).

Functional abnormalities of intracellular signaling network cause the disruption in homeostasis maintained by critical cellular components, thereby accelerating premalignant and malignant transformation. Multiple lines of evidence suggest that an elevated expression of cyclooxygenase-2 (COX-2) is causally linked to tumorigenesis. The exposure to oxidative/pro-inflammatory stimuli turns on signaling arrays mediated by diverse classes of kinases and transcription factors, which may lead to aberrant expression of COX-2. We have attempted to unravel the signal transduction pathways involved in elevated COX-2 expression in mouse skin stimulated with a prototype tumor promoter 12- O-tetradecanoylphorbol-13-acetate (TPA) and its modulation by resveratrol, a phytoalexin known to exert potential chemopreventive effects. Our study revealed that topical application of TPA induced COX-2 expression in mouse skin via activation of nuclear factor-κB (NF-κB), which is regulated by upstream IκB kinase (IKK) or differentially by mitogen-activated protein (MAP) kinases. Besides NF-κB, the p38 MAP kinase-mediated activation of activator protein-1 (AP-1) has also been attributed to TPA-induced COX-2 expression in mouse skin. Among the MAP kinases, extracellular signal-regulated protein kinase (ERK) and p38 MAP kinase have been shown to regulate TPA-induced NF-κB activation, while p38 MAP kinase and c-Jun-N-terminal kinase are preferentially involved in TPA-induced activation of AP-1 in mouse skin in vivo. This commentary focuses on resveratrol modulation of intracellular signaling pathways involved in aberrant COX-2 expression in TPA-stimulated mouse skin to delineate molecular mechanisms underlying antitumor promoting effects of resveratrol.

Keywords: Abbreviations; AP-1; activator protein-1; C/EBP; CCAAT/enhancer binding protein; CREB; cyclic AMP response element binding protein; CBP; CREB binding protein; COX-2; cyclooxygenase-2; DMBA; 7,12-dimethylbenz[; a; ]anthracene; ERK; extracellular signal-regulated protein kinase; IKK; IκB kinase; JNK; c-Jun-N-terminal kinase; MAP kinase; mitogen-activated protein kinase; NF-κB; nuclear factor-kappaB; PG; prostaglandin; PI3K; phosphoinositide 3-kinase; PKC; protein kinase C; TPA; 12-; O; -tetradecanoylphorbol-13-acetateResveratrol; Phorbol ester; Cyclooxygenase-2; Transcription factors; IκB kinase; Mitogen-activated protein kinase; Mouse skin

15-Deoxy-Δ^12,14-prostaglandin J₂ as a potential endogenous regulator of redox-sensitive transcription factors by Eun-Hee Kim; Young-Joon Surh (pp. 1516-1528).

15-Deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) has been known to display multifaceted cellular functions, including anti-inflammatory and cytoprotective effects. However, depending on the concentrations and intracellular microenvironment, this cyclopentenone prostaglandin can exert opposite effects. Because of the α,β-unsaturated carbonyl moiety present in its cyclopentenone ring structure, 15d-PGJ₂ can act as a Michael reaction acceptor and readily interacts with critical cellular nucleophiles, such as cysteine thiol groups in proteins. Many of the biological effects induced by 15d-PGJ₂ involve redox-transcription factors as the potential targets. Thus, 15d-PGJ₂ can modulate the transcriptional activities of nuclear factor-κB (NF-κB), activator protein-1 (AP-1), nuclear factor-erythroid 2p45 (NF-E2)-related factors (Nrf2), hypoxia inducible factor (HIF), etc. 15d-PGJ₂ is also well known as an endogenous ligand of peroxisome proliferator-activated receptor γ (PPARγ). However, the regulation of the aforementioned redox-sensitive transcription factors by 15d-PGJ₂ is not necessarily mediated via PPARγ activation, but rather involves covalent modification or oxidation of their critical cysteine residues acting as a redox-sensor. This commentary describes the biological and physiological functions of 15d-PGJ₂ and underlying biochemical and molecular mechanisms with emphasis on the modulation of redox-sensitive transcription factors and their regulators.

Keywords: Abbreviations; AP-1; activator protein-1; ARE/EpRE; antioxidant/electrophile response element; COX; cyclooxygenase; cyPGs; cyclopentenone prostaglandins; 15d-PGJ; ₂; 15-deoxy-Δ; ^12,14; -prostaglandin J; ₂; γ-GCL; γ-glutamate cysteine ligase; GSTs; glutathione; S; -transferases; HIF; hypoxia inducible factor; HO-1; heme oxygenase-1; HRE; hypoxia response element; iNOS; inducible nitric oxide synthase; Keap1; Kelch-like ECH-associated protein 1; MAPKs; mitogen-activated protein kinases; NF-κB; nuclear factor-κB; NQO1; NAD(P)H: quinone oxidoreductase 1; Nrf2; nuclear factor-erythroid 2p45 (NF-E2)-related factors; PPARγ; peroxisome proliferator-activated receptor γ; PPRE; PPAR response elements; RXR; receptor for 9 cis-retinoid; STAT; signal transducer and activator of transcription; TPA; 12-; O; -tetradecanoylphorbol-13-acetate15-Deoxy-Δ; ^12,14; -prostaglandin; Redox regulation; Thiol modification; Transcription factors; PPARγ; NF-κB; AP-1; Nrf2

Tissue specific glucocorticoid receptor expression, a role for alternative first exon usage? by Jonathan D. Turner; Andrea B. Schote; Joana A. Macedo; Laetitia P.L. Pelascini; Claude P. Muller (pp. 1529-1537).

The CpG island upstream of the GR is highly structured and conserved at least in all the animal species that have been investigated. Sequence alignment of these CpG islands shows inter-species homology ranging from 64 to 99%. This 3.1kb CpG rich region upstream of the GR exon 2 encodes 5′ untranslated mRNA regions. These CpG rich regions are organised into multiple first exons and, as we and others have postulated, each with its own promoter region. Alternative mRNA transcript variants are obtained by the splicing of these alternative first exons to a common acceptor site in the second exon of the GR. Exon 2 contains an in-frame stop codon immediately upstream of the ATG start codon to ensure that this 5′ heterogeneity remains untranslated, and that the sequence and structure of the GR is unaffected.Tissue specific differential usage of exon 1s has been observed in a range of human tissues, and to a lesser extent in the rat and mouse. The GR expression level is tightly controlled within each tissue or cell type at baseline and upon stimulation. We suggest that no single promoter region may be capable of containing all the necessary promoter elements and yet preserve the necessary proximity to the transcription initiation site to produce such a plethora of responses. Thus we further suggest that alternative first exons each under the control of specific transcription factors control both the tissue specific GR expression and are involved in the tissue specific GR transcriptional response to stimulation. Spreading the necessary promoter elements over multiple promoter regions, each with an associated alternative transcription initiation site would appear to vastly increase the capacity for transcriptional control of GR.

Keywords: Abbreviations; ALL; acute lymphoblastic leukaemia; EST; expression sequence tag; GC; glucocorticoid; GR; glucocorticoid receptor; HPA; hypothalamic–pituitary–adrenal; NGFI-A; nerve growth factor inducible protein A; RACE; rapid amplification of complimentary ends; UTR; untranslated region; YY1; Yin Yang 1Glucocorticoid receptor; NR3C1; 5′ untranslated region; Alternative exon splicing

Jaks and cytokine receptors—An intimate relationship by Claude Haan; Stephanie Kreis; Christiane Margue; Iris Behrmann (pp. 1538-1546).

Most cytokine receptors lack intrinsic kinase activity and many of them signal via Janus kinases (Jaks). These tyrosine kinases are associated with cytokine receptor subunits, they become activated upon receptor triggering and subsequently activate downstream signalling events, e.g. the phosphorylation of STAT transcription factors.The successful interplay between cytokines, their receptors and the connected Jaks not only determines signalling competence but is also vital for intracellular traffic, stability, and fate of the cognate receptors. Here, we will discuss underlying mechanisms as well as some structural features with a focus on Jak1 and two of the signal transducing receptor subunits of interleukin (IL)-6 type cytokines, gp130 and OSMR.Regions that are critically involved in Jak-binding have been identified for many cytokine receptor subunits. In most cases the membrane-proximal parts comprising the box1 and box2 regions within the receptor are involved in this association while, within Jaks, the N-terminal FERM domain, possibly together with the SH2-like domain, are pivotal for binding to the relevant receptors. The exclusive membrane localisation of Jaks depends on their ability to associate with cytokine receptors. For gp130 and Jak1, it was shown that the cytokine receptor/Jak complex can be regarded as a receptor tyrosine kinase since both molecules have the same diffusion dynamics and are virtually undissociable. Furthermore, Jaks take an active role in the regulation of the surface expression of at least some cytokine receptors, including the OSMR and this may provide a quality control mechanism ensuring that only signalling-competent receptors (i.e. those with an associated Jak) would be enriched at the cell surface.

Keywords: Abbreviations; EPO; erythropoietin; FERM; four-point-one, ezrin, radixin, moesin; IFN; interferon; IL; interleukin; Jak; Janus kinase; JH; Jak homology; LIF; leukaemia inhibitory factor; OSM; oncostatin M; R; receptor; SCID; severe combined immunodeficiency; SH2; src-homology 2; STAT; signal transducer and activator of transcription; YFP; yellow fluorescent proteinJanus kinase; Cytokine receptor; FERM domain; SH2 domain; Protein trafficking; STAT

Curcumin regulates signal transducer and activator of transcription (STAT) expression in K562 cells by Romain Blasius; Simone Reuter; Estelle Henry; Mario Dicato; Marc Diederich (pp. 1547-1554).

Signal transducers and activators of transcription (STATs) play important roles in numerous cellular events as for example differentiation, inflammation or immune response. Furthermore, constitutive STAT activation can be observed in a high number of tumors. In our hands, curcumin treatment induced a decrease of nuclear STAT3, -5a and -5b, without affecting neither STAT1, nor the phosphorylation state of STAT1, -3 or -5 in the K562 cell line. Most interestingly, the decrease of nuclear STAT5a and -5b after curcumin treatment was accompanied by an increase of truncated STAT5 isoforms, indicating that curcumin is able to induce the cleavage of STAT5 into its dominant negative variants lacking the STAT5 C-terminal region. Interferon (IFN)-β and -γ treatment induced IFN-stimulated responsive element (ISRE) transcriptional activity, which was efficiently inhibited by curcumin pre-treatment. In parallel, IFN-γ treatment induced an increase of the amount of nuclear STAT1 and -3, as well as their phosphorylated isoforms. Again, curcumin pre-treatment inhibited these increases. Finally, curcumin treatment inhibited Jak2 mRNA expression as well as cyclin D1 and v-src gene expression in K562 chronic leukaemia cells.

Keywords: Abbreviations; STAT; signal transducer and activator of transcription; IFN; interferon; IL; interleukin; ISRE; interferon-stimulated response element; Jak; Janus kinase; FCS; foetal calf serumSTAT; Curcumin; K562; IFN

Suppression of IL-1β expression by the Jak 2 inhibitor AG490 in cerulein-stimulated pancreatic acinar cells by Ji Hoon Yu; Kyung Hwan Kim; Hyeyoung Kim (pp. 1555-1562).

Cerulein pancreatitis is similar to human edematous pancreatitis with dysregulation of the digestive enzyme production and cytoplasmic vacuolization, the death of acinar cells, edema formation, and an infiltration of inflammatory cells into the pancreas. Cytokines are up-regulated in pancreatic acinar cells stimulated with cerulein. In various cells and tissues, Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway mediates inflammatory process. In the present study, we investigated whether the activation of Jak/Stat signaling mediates IL-1β expression in pancreatic acinar AR42J cells stimulated with cerulein in vitro as well as the rats with cerulein pancreatitis in vivo using AG490, the Jak2 inhibitor. Activation of Jak2 and Stat3 were monitored by Western blot analysis for phosphorylated Jak2 and phosphorylated Stat3. mRNA expression and protein level of IL-1β were determined by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbant assay (ELISA). Histological examination of pancreatic tissues were performed and serum IL-1β levels of the rats were determined by ELISA. As a result, cerulein induced the activation of Jak2 and Stat3 as well as IL-1β expression, which was inhibited by the treatment of AG490 in AR42J cells. In cerulein pancreatitis of the rats, edematous and inflammatory changes of the pancreas and increased serum levels of IL-1β were suppressed by AG490 treatment. In conclusion, Jak2/Stat3 pathway may be the underlying mechanism in the pathogenesis of pancreatitis by inducing cytokines such as IL-1β.

Keywords: Cerulein; IL-1β; Jak/Stat; AG490; Pancreatic acinar cells

Chromatin structure and epigenetics by A.S. Quina; M. Buschbeck; L. Di Croce (pp. 1563-1569).

In eukaryotic cells, the DNA molecule is found in the form of a nucleoprotein complex named chromatin. The basic unit of the chromatin is the nucleosome, which comprises 147 base pairs of DNA wrapped around an octamer of core histones (made of two molecules of each H2A, H2B, H3, and H4 histones). Each nucleosome is linked to the next by small segments of linker DNA. Most chromatin is further condensated by winding in a polynucleosome fibre, which may be stabilized through the binding of histone H1 to each nucleosome and to the linker DNA.The modulation of the structure of the chromatin fibre is critical for the regulation of gene expression since it determines the accessibility and the sequential recruitment of regulatory factors to the underlying DNA. Depending on the different transcriptional states, the structure of the chromatin may be altered in its constituents (e.g. the presence of repressors, activators, chromatin remodelling complexes, and/or incorporation of histone variants), and in covalent modifications of its constituents (such as DNA methylation at cytosine residues, and posttranslational modifications of histone tails). Here, we give an overview of the molecular mechanisms involved in chromatin regulation and the epigenetic transmission of its state, both in normal and pathological scenarios.

Keywords: Abbreviations; APL; acute promyelocytic leukemias; DNMT; DNA methyltransferase; HAT; histone acetyltransferase; HDAC; histone deacetylase; HMTs; histone methyltransferases; MBDs; methyl-binding proteins; PML; promyelocytic leukemia gene; RAR; retinoic acid receptorChromatin structure; DNA methylation; Epigenetics; Leukemia; PML-RARα

Epigenetic silencing of MHC2TA transcription in cancer by Tjadine M. Holling; Marja C.J.A. van Eggermond; Martine J. Jager; Peter J. van den Elsen (pp. 1570-1576).

Lack of expression of major histocompatibility complex (MHC) molecules of both classes is frequently noted on tumour cells . It is thought that in this way tumour cells escape immunosurveillance. The genes encoding both classes of MHC molecules are localized on the distal part of chromosome 6 (6p21.3). The class II transactivator (CIITA), encoded by the MHC2TA gene, is essential for transcriptional activation of all MHC-II genes, while it has a helper function in the transcriptional regulation of MHC-I genes (with the exception of human leukocyte antigen ( HLA)- G) and of the gene encoding β2-microglobulin ( β2m) . Here we discuss our current knowledge on the expression characteristics of MHC2TA and argue for an important role of epigenetic factors and mechanisms in the transcriptional silencing of MHC2TA in cancer cells.

Keywords: Major histocompatibility complex class II; Class II transactivator; Cancer; Gene regulation; DNA methylation; Histone modification

Epigenetic control of CTCFL/BORIS and OCT4 expression in urogenital malignancies by Michèle J. Hoffmann; Mirko Müller; Rainer Engers; Wolfgang A. Schulz (pp. 1577-1588).

Aberrant hypomethylation in many cancers reactivates retrotransposons and selected single-copy genes such as cancer-testis antigens. Genes reactivated in this manner have recently been postulated to include CTCFL/ BORIS, a presumptive testis-specific chromatin regulator, and OCT4/ POU5F1, a transcriptional activator in pluripotent cells. We found both genes expressed at high levels in testis and at much lower levels in normal prostate tissue. In prostate and bladder carcinoma cell lines and cancer tissues expression remained largely unchanged, but individual prostate carcinomas showed modestly increased CTCFL expression compared to normal tissues. OCT4 expression was significantly decreased in cancer tissues. Promoter methylation in both genes paralleled expression levels. CTCFL, but not OCT4 was dramatically induced in cancer cell lines by 5-aza-2′-deoxycytidine, but neither gene by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. Thus, CTCFL and OCT4 resemble cancer-testis antigens in being selectively hypomethylated and expressed in male germ cells but differ in lacking significant reexpression and hypomethylation in prostate carcinomas. DNA methylation appears the crucial mechanism in the control of CTCFL transcription, but less decisive in that of OCT4. These findings imply that inhibitors of DNA methylation used for cancer treatment may induce CTCFL expression. Immunohistochemistry demonstrated nuclear localization of CTCFL in developing spermatocytes, and cytoplasmatic localization in spermatogonia, Leydig cells, and epithelial prostate cells. Teratocarcinoma cell lines showed nuclear, and 5-aza-2′-deoxycytidine-treated prostate cancer lines nuclear or cytoplasmatic localization. These different localizations might indicate additional control of CTCFL function via intracellular compartmentation.

Keywords: Abbreviations; 5-aza-dC; 5-aza-2′-deoxycytidine; SAHA; suberoylanilide hydroxamic acid; TSA; trichostatin A; UEC; normal uroepithelial cellsBORIS; OCT4; Cancer-testis antigen; DNA hypomethylation; 5-Aza-2′-deoxycytidine; HDAC inhibitors

Epigenetic regulation of nuclear steroid receptors by Jennifer E. Leader; Chenguang Wang; Maofu Fu; Richard G. Pestell (pp. 1589-1596).

Histone modifier proteins have come to the forefront in the study of gene regulation. It is now known that histone methyltransferases, acetytransferases, kinases, ubiquitinases, deacetylases and demethylases orchestrate expression of target genes by modifying both histone and non-histone proteins. The nuclear receptor (NR) superfamily govern such diverse biological processes as development, physiology and disease, including human cancer. The involvement of NR in complexes with coactivators and corepressors is necessary for regulation of target genes. This review focuses on the newly recognized interactions between the NR and histone modifying enzymes. In addition to regulating histones, the histone modifying proteins directly modify and thereby regulate NR activity. In the same manner that signaling platforms exist within the histone tails that are post-translationally processed by histone modifying proteins, cascades of post-translational modification have been identified within the NR that coordinate their activity. This review focuses on the regulation of the NR estrogen receptor (ERα), androgen receptor (AR) and peroxisome proliferator activated receptor-gamma (PPARγ), given their role in tumor onset and progression.

Keywords: Abbreviations; NR; nuclear receptor; AR; androgen receptor; ERα; estrogen receptor; PPARγ; peroxisome proliferator-activated receptor γ; HAT; histone acetyltransferase; HDAC; histone deacetylase; SRC; steroid receptor coactivator; N-CoR; nuclear receptor corepresssor; SMRT; silencing mediator of retinoid and thyroid hormone receptor; TSA; trichostatin A; SIRT1; Sirtuin 1; CBP; CREB binding protein; p/CAF; p300/CBP-associated factor; DNMT; DNA methyltransferase; ChIP; chromatin immunoprecipitation; LSD1; lysine specific demethylaseNuclear receptors; Androgen receptor; Estrogen receptor; Peroxisome proliferator activated receptor; Epigenetics; Histone

Regulation of the hypertonic stress response and other cellular functions by the Rel-like transcription factor NFAT5 by José Aramburu; Katherine Drews-Elger; Anaïs Estrada-Gelonch; Jordi Minguillón; Beatriz Morancho; Verónica Santiago; Cristina López-Rodríguez (pp. 1597-1604).

Stress, be it from environmental factors or intrinsic to the cell as result of growth and metabolism can be harmful to cells. Mammalian cells have developed numerous mechanisms to respond to diverse forms of stress. These mechanisms combine signaling cascades and activation of gene expression programs to orchestrate an adaptive response that will allow the cell to survive and resume its normal functioning. In this review we will focus on the transcription factor NFAT5, a fundamental regulator of the response to osmotic stress in mammalian cells. Identified in 1999, NFAT5 is the latest addition to the Rel family, which comprises the NF-κB and NFATc proteins. Though in some of its structural and functional features NFAT5 is a hybrid between these two major groups of Rel proteins, it has unique characteristics that make it stand on its own as a third type of Rel transcription factor. Since its discovery, NFAT5 has been studied mostly in the context of the hypertonicity stress response. The advent of mouse models deficient in NFAT5 and other recent advances have confirmed a fundamental osmoprotective role for this factor in mammals, but also revealed features that suggest it may have a wider range of functions.

Keywords: Rel transcription factors; NFAT5; Hypertonic stress; Gene expression

Inflammation and cancer: How hot is the link? by Bharat B. Aggarwal; Shishir Shishodia; Santosh K. Sandur; Manoj K. Pandey; Gautam Sethi (pp. 1605-1621).

Although inflammation has long been known as a localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function, there has been a new realization about its role in a wide variety of diseases, including cancer. While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, cardiovascular, pulmonary, and neurological diseases. Several pro-inflammatory gene products have been identified that mediate a critical role in suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis. Among these gene products are TNF and members of its superfamily, IL-1α, IL-1β, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX. The expression of all these genes are mainly regulated by the transcription factor NF-κB, which is constitutively active in most tumors and is induced by carcinogens (such as cigarette smoke), tumor promoters, carcinogenic viral proteins (HIV-tat, HIV-nef, HIV-vpr, KHSV, EBV-LMP1, HTLV1-tax, HPV, HCV, and HBV), chemotherapeutic agents, and γ-irradiation. These observations imply that anti-inflammatory agents that suppress NF-κB or NF-κB-regulated products should have a potential in both the prevention and treatment of cancer. The current review describes in detail the critical link between inflammation and cancer.

Keywords: Abbreviations; ALL; acute lymphocytic anemia; AML; acute myelogenous leukemia; B-CLL; B-cell chronic lymphocytic leukemia; CLL; chronic lymphocytic leukemia; COX; cyclooxygenase; EBV-LMP1; Epstein-Barr virus-latent membrane protein; EGFR; epidermal growth factor receptor; HBV; hepatitis B virus; HCL; hairy cell leukemia; HCV; hepatitis C virus; HPV; human papilloma virus; IκB; inhibitory subunit of NF-κB; IL; interleukin; iNOS; inducible nitric oxide synthase; LOX; lipoxygenase; MAPK; mitogen-activated protein kinase; MMP; matrix metalloproteinase; NF-κB; nuclear factor-κB; PPAR-γ; peroxisome proliferator activated receptors; RCC; renal cell carcinoma; TGFα; transforming growth factor; TNF-α; tumor necrosis factor; VCAM-1; vascular cell adhesion molecule 1; VEGF; vascular endothelial growth factorNF-κB; TNF; Interleukins; Chemokines; COX; LOX

S100A8 and S100A9 in inflammation and cancer by Christoffer Gebhardt; Julia Németh; Peter Angel; Jochen Hess (pp. 1622-1631).

Calprotectin (S100A8/A9), a heterodimer of the two calcium-binding proteins S100A8 and S100A9, was originally discovered as immunogenic protein expressed and secreted by neutrophils. Subsequently, it has emerged as important pro-inflammatory mediator in acute and chronic inflammation. More recently, increased S100A8 and S100A9 levels were also detected in various human cancers, presenting abundant expression in neoplastic tumor cells as well as infiltrating immune cells. Although, many possible functions have been proposed for S100A8/A9, its biological role still remains to be defined. Altogether, its expression and potential cytokine-like function in inflammation and in cancer suggests that S100A8/A9 may play a key role in inflammation-associated cancer.

Keywords: Abbreviations; DMBA; 7,12-dimethylbenz(a)anthracene; TPA; 12-; O; -tetradecanoylphorbol-13-acetate; SCC; squamous cell carcinoma; AP-1; activator protein-1; NF-κB; nuclear factor-κB; JNK; Jun N-terminal kinase; AGEs; advanced glycation end-products; RAGE; receptor of advanced glycation end-productsS100; RAGE; AP-1; NF-κB; Inflammation; Carcinogenesis

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Biochemical Pharmacology (v.72, #11)