B‐Raf/Rap1 signaling, but not c‐Raf‐1/Ras, induces the histidine decarboxylase promoter in<i>Helicobacter pylori</i>infection

Weßler, Silja; Rapp, Ulf R.; Wiedenmann, Bertram; Meyer, Thomas F.; Schöneberg, Torsten; Höcker, Michael; Naumann, Michael

doi:10.1096/fj.01-0766fje

Cited by 43 publications

(26 citation statements)

References 47 publications

(69 reference statements)

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“…The relationship between the ERK pathway and the cag PAI in gastric epithelial cells remains unsettled, as several studies have reported that the cag PAI is involved in ERK phosphorylation (12,13,19), whereas other studies have not supported this relationship (25,32,33,38). In our previous study, neither the cag PAI nor OipA was involved in the phosphorylation of ERK in MKN45 cells (38).…”

Section: Discussionmentioning

confidence: 69%

Regulation of RANTES Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

Kudo

Lü

et al. 2005

Infect Immun

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RANTES, a CC chemokine, plays an important role in the inflammatory response associated with Helicobacter pylori infection. However, the mechanism by which H. pylori induces RANTES expression in the gastric mucosa is unknown. We cocultured gastric epithelial cells with wild-type H. pylori, isogenic oipA mutants, cag pathogenicity island (PAI) mutants, or double knockout mutants. Reverse transcriptase PCR showed that RANTES mRNA was induced by H. pylori and that the expression was both OipA and cag PAI dependent. Luciferase reporter gene assays and electrophoretic mobility shift assays showed that maximal H. pyloriinduced RANTES gene transcription required the presence of the interferon-stimulated responsive element (ISRE), the cyclic AMP-responsive element (CRE), nuclear factor-interleukin 6 (NF-IL-6), and two NF-B sites. OipA-and cag PAI-dependent pathways included NF-B3NF-B/NF-IL-6/ISRE pathways, and cag PAI-dependent pathways additionally included Jun N-terminal kinase3CRE/NF-B pathways. The OipAdependent pathways additionally included p383CRE/ISRE pathways. We confirmed the in vitro effects in vivo by examining RANTES mRNA levels in biopsy specimens from human gastric antral mucosa. RANTES mRNA levels in the antral mucosa were significantly higher for patients infected with cag PAI/OipA-positive H. pylori than for those infected with cag PAI/OipA-negative H. pylori or uninfected patients. The mucosal inflammatory response to H. pylori infection involves different signaling pathways for activation of the RANTES promoter, with both OipA and the cag PAI being required for full activation of the RANTES promoter. Gastric epithelial damage inHelicobacter pylori infection is thought to be related to the cellular and humoral inflammatory response to the infection. The cellular immune response to the organism initially consists of the recruitment of neutrophils, followed by T and B lymphocytes, plasma cells, and macrophages. Members of the chemokine supergene family, particularly the CXC and CC chemokine subfamilies, are thought to be responsible for recruitment of these inflammatory cells into the gastric mucosa (7,8,14,28,31,(35)(36)(37). RANTES (regulated on activation normal T cell expressed and secreted) is a CC chemokine produced by epithelial cells, CD8 ϩ T cells, fibroblasts, and platelets that mediates the trafficking and homing of classical lymphoid cells such as T cells and monocytes. RANTES also acts on a range of other cells, including basophils, eosinophils, natural killer cells, dendritic cells, and mast cells (2, 30).Increased RANTES production is a feature of H. pyloriinduced gastric inflammation (7,14,28,31,37). RANTES mRNA expression is also thought to play an important role in maintaining residual memory T lymphocytes and eosinophils in gastric mucosa following H. pylori eradication (14). The mechanisms responsible for inducible RANTES gene transcription associated with H. pylori infections have not been fully elucidated. Mori et al. (23) recently reported that the regulation of RANTES gene trans...

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Section: Discussionmentioning

confidence: 69%

Regulation of RANTES Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

Kudo

Lü

et al. 2005

Infect Immun

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“…Also, Rap1 regulates cell morphogenetic processes (63). Recently, Wessler et al (64) reported that infection of cagA-positive H. pylori activated the Rap1/B-Raf pathway but not the Ras/Raf-1 pathway in AGS cells. Therefore, the CagA-SHP-2 complex might activate the Rap1/B-Raf pathway and induce sustained Erk activation, which is associated with the morphological change.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation

Higashi

Nakaya

Tsutsumi

et al. 2004

Journal of Biological Chemistry

257

242

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The CagA protein of Helicobacter pylori, which is injected from the bacteria into bacteria-attached gastric epithelial cells, is associated with gastric carcinoma. CagA is tyrosine-phosphorylated by Src family kinases, binds the SH2 domain-containing SHP-2 phosphatase in a tyrosine phosphorylation-dependent manner, and deregulates its enzymatic activity. We established AGS human gastric epithelial cells that inducibly express wildtype or a phosphorylation-resistant CagA, in which tyrosine residues constituting the EPIYA motifs were substituted with alanines. Upon induction, wild-type CagA, but not the mutant CagA, elicited strong elongation of cell shape, termed the "hummingbird" phenotype. Time-lapse video microscopic analysis revealed that the CagA-expressing cells exhibited a marked increase in cell motility with successive rounds of elongation-contraction processes. Inhibition of CagA phosphorylation by an Src kinase inhibitor, PP2, or knockdown of SHP-2 expression by small interference RNA (siRNA) abolished the CagA-mediated hummingbird phenotype. The morphogenetic activity of CagA also required Erk MAPK but was independent of Ras or Grb2. In AGS cells, CagA prolonged duration of Erk activation in response to serum stimulation. Conversely, inhibition of SHP-2 expression by siRNA abolished the sustained Erk activation. Thus, SHP-2 acts as a positive regulator of Erk activity in AGS cells. These results indicate that SHP-2 is involved in the Ras-independent modification of Erk signals that is necessary for the morphogenetic activity of CagA. Our work therefore suggests a key role of SHP-2 in the pathological activity of H. pylori virulence factor CagA.

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“…A-Raf is the least-studied kinase in the Raf family and its contribution to the MAPK signaling pathway has yet to be clarified (15). It is interesting to note that a recent study showed that B-Raf/Rap1 signaling, but not c-Raf-1/Ras, induces the histidine decarboxylase promoter in Heliobacter pylori infection (34), indicating that B-raf/Rap1 and Raf-1/Ras are independent upstream activators of the MEK/ERK-signaling cascade.…”

Section: Discussionmentioning

confidence: 99%

Tuberous sclerosis-2 tumor suppressor modulates ERK and B-Raf activity in transformed renal epithelial cells

Yoon

Ramachandiran

Chacko

et al. 2004

American Journal of Physiology-Renal Physiology

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. Tuberous sclerosis-2 tumor suppressor modulates ERK and B-Raf activity in transformed renal epithelial cells. Am J Physiol Renal Physiol 286: F417-F424, 2004. First published November 11, 2003 10.1152/ ajprenal.00234.2003.-The tuberous sclerosis-2 (Tsc-2) gene is a suppressor of renal tumorigenesis and an early target of reactive oxygen species-induced renal cancer. Tuberin, the protein product of the Tsc-2 gene, participates in the regulation of cell proliferation, although the mechanism by which it suppresses proliferation is unknown. Quinol-thioether-transformed rat renal epithelial (QT-RRE) cell lines, derived from quinol-thioether-transformed primary renal epithelial cells from Eker rats, lack tuberin expression due to loss of heterozygosity of the Tsc-2 gene. These cell lines were used to examine the mechanism by which tuberin exerts its antiproliferative action. Loss of tuberin function correlates with high ERK activity (39), which could contribute to the formation of renal tumors. In this study, we sought to identify possible downstream effectors regulated by tuberin, using QT-RRE cells transfected with Tsc-2 cDNA to restore tuberin expression. Constitutively high ERK, B-Raf, and Raf-1 activities were observed in QT-RRE cells. However, restoration of tuberin expression in QT-RRE cells by transient transfection with Tsc-2 cDNA substantially decreased both ERK and B-Raf activity, with only modest changes in Raf-1 activity, suggesting tuberin functions as an upstream negative regulator of the ERK pathway. High ERK activity was not mediated through EGF receptor activation, but treatment with genistein demonstrated that protein kinases are involved in ERK cascade activation. The data indicate that loss of tuberin results in the upregulation of the ERK signaling pathway with subsequent increases in new DNA synthesis, and ultimately, tumor formation.cell cycle extracellular signal-regulated kinase; quinol-thioether reactive oxygen species THE TUBEROUS SCLEROSIS-2 (Tsc-2) gene functions as a renal tumor suppressor (33), although the mechanism of this effect remains elusive (25,35,38). Tuberin, the Tsc-2-encoded protein, regulates cell growth and proliferation (1,9,23,24,27) and cell cycle progression (25,26). Loss of tuberin expression induces quiescent G 0 -arrested cells to enter the cell cycle and prevents cells from reentering a quiescent state (25). Similarly, a reduction in the level of tuberin increases cyclin D 1 protein expression and promotes the transition from G 0 /G 1 to S phase. Inactivation of gigas, the Drosophila homolog of Tsc-2, results in the formation of tissues composed of enlarged cells with a repeating S phase without entering the M phase (8).The mechanism underlying the antiproliferative function of tuberin is still relatively uncharacterized. Recent studies showed that the Akt pathway regulates the formation of the tuberous sclerosis complex (7). Components of this complex, in turn, inhibit signaling mediated by the mammalian target of rapamycin (28). Tuberin is a structurally compl...

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B‐Raf/Rap1 signaling, but not c‐Raf‐1/Ras, induces the histidine decarboxylase promoter inHelicobacter pyloriinfection

Cited by 43 publications

References 47 publications

Regulation of RANTES Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

Regulation of RANTES Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation

Tuberous sclerosis-2 tumor suppressor modulates ERK and B-Raf activity in transformed renal epithelial cells

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