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Article ; Online: c-jun is differentially expressed in embryonic and adult neural precursor cells.

Kawashima, Fumiaki / Saito, Kengo / Kurata, Hirofumi / Maegaki, Yoshihiro / Mori, Tetsuji

2017 Volume 147, Issue 6, Page(s) 721–731

Abstract: c-jun, a major component of AP-1 transcription factor, has a wide variety of functions ... In the embryonic brain, c-jun mRNA is abundantly expressed in germinal layers around the ventricles ... precursor cells (NPCs), the c-jun expression pattern is not clear. To study the function of c-jun in adult ...

Abstract	c-jun, a major component of AP-1 transcription factor, has a wide variety of functions. In the embryonic brain, c-jun mRNA is abundantly expressed in germinal layers around the ventricles. Although the subventricular zone (SVZ) of the adult brain is a derivative of embryonic germinal layers and contains neural precursor cells (NPCs), the c-jun expression pattern is not clear. To study the function of c-jun in adult neurogenesis, we analyzed c-jun expression in the adult SVZ by immunohistochemistry and compared it with that of the embryonic brain. We found that almost all proliferating embryonic NPCs expressed c-jun, but the number of c-jun immunopositive cells among proliferating adult NPCs was about half. In addition, c-jun was hardly expressed in post-mitotic migrating neurons in the embryonic brain, but the majority of c-jun immunopositive cells were tangentially migrating neuroblasts heading toward the olfactory bulb in the adult brain. In addition, status epilepticus is known to enhance the transient proliferation of adult NPCs, but the c-jun expression pattern was not significantly affected. These expression patterns suggest that c-jun has a pivotal role in the proliferation of embryonic NPCs, but it has also other roles in adult neurogenesis.
Language	English
Publishing date	2017-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1222930-1
ISSN	1432-119X ; 0301-5564 ; 0948-6143
ISSN (online)	1432-119X
ISSN	0301-5564 ; 0948-6143
DOI	10.1007/s00418-016-1536-2
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Article ; Online: Augmentation of invadopodia formation in temozolomide-resistant or adopted glioma is regulated by c-Jun terminal kinase-paxillin axis.

Ueno, Hideaki / Tomiyama, Arata / Yamaguchi, Hideki / Uekita, Takamasa / Shirakihara, Takuya / Nakashima, Katsuhiko / Otani, Naoki / Wada, Kojiro / Sakai, Ryuichi / Arai, Hajime / Mori, Kentaro

Biochemical and biophysical research communications

2015 Volume 468, Issue 1-2, Page(s) 240–247

Abstract: ... mitogen-activated protein kinase signals found increased phosphorylation of c-Jun terminal kinase (JNK) and higher activation ...

Abstract	Temozolomide (TMZ) is one of the few effective anticancer agents against gliomas. However, acquisition of TMZ resistance or adaptation by gliomas is currently a crucial problem, especially increased invasiveness which is critical for the determination of clinical prognosis. This study investigated the molecular regulatory mechanisms of TMZ resistance in gliomas involved in invasiveness, particularly invadopodia formation, a molecular complex formed at the invasive front to cause extracellular matrix degradation during cellular local invasion. The TMZ-resistant clone of the U343 MG human glioma cell line (U343-R cells) was established. U343-R cells demonstrated higher invadopodia formation compared with U343 cells without TMZ resistance (U343-Con cells). Immunoblot analysis of DNA damage-related mitogen-activated protein kinase signals found increased phosphorylation of c-Jun terminal kinase (JNK) and higher activation of its downstream signaling in U343-R cells compared with U343-Con cells. Treatment of U343-R cells with specific inhibitors of JNK or siRNA targeting JNK suppressed up-regulation of invadopodia formation. In addition, paxillin, one of the known JNK effectors which is phosphorylated and affects cell migration, was phosphorylated at serine 178 in JNK activity-dependent manner. Expression of paxillin with mutation of the serine 178 phosphorylation site in U343-R cells blocked invadopodia formation. The present findings suggest that increased formation of invadopodia in U343-R cells is mediated by hyperactivation of JNK-paxillin signaling, and both JNK and paxillin might become targets of novel therapies against TMZ-resistant gliomas.
MeSH term(s)	Antineoplastic Agents, Alkylating/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Dacarbazine/analogs & derivatives ; Dacarbazine/pharmacology ; Drug Resistance, Neoplasm ; Glioma/drug therapy ; Glioma/metabolism ; Glioma/pathology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Paxillin/metabolism ; Phosphorylation/drug effects ; Podosomes/drug effects ; Podosomes/metabolism ; Podosomes/pathology ; Signal Transduction/drug effects
Chemical Substances	Antineoplastic Agents, Alkylating ; Paxillin ; Dacarbazine (7GR28W0FJI) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; temozolomide (YF1K15M17Y)
Language	English
Publishing date	2015-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2015.10.122
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Article: Augmentation of invadopodia formation in temozolomide-resistant or adopted glioma is regulated by c-Jun terminal kinase–paxillin axis

Ueno, Hideaki / Tomiyama, Arata / Yamaguchi, Hideki / Uekita, Takamasa / Shirakihara, Takuya / Nakashima, Katsuhiko / Otani, Naoki / Wada, Kojiro / Sakai, Ryuichi / Arai, Hajime / Mori, Kentaro

Biochemical and biophysical research communications. 2015 Dec. 04, v. 468

2015

Abstract: ... mitogen-activated protein kinase signals found increased phosphorylation of c-Jun terminal kinase (JNK) and higher activation ...

Abstract	Temozolomide (TMZ) is one of the few effective anticancer agents against gliomas. However, acquisition of TMZ resistance or adaptation by gliomas is currently a crucial problem, especially increased invasiveness which is critical for the determination of clinical prognosis. This study investigated the molecular regulatory mechanisms of TMZ resistance in gliomas involved in invasiveness, particularly invadopodia formation, a molecular complex formed at the invasive front to cause extracellular matrix degradation during cellular local invasion. The TMZ-resistant clone of the U343 MG human glioma cell line (U343-R cells) was established. U343-R cells demonstrated higher invadopodia formation compared with U343 cells without TMZ resistance (U343-Con cells). Immunoblot analysis of DNA damage-related mitogen-activated protein kinase signals found increased phosphorylation of c-Jun terminal kinase (JNK) and higher activation of its downstream signaling in U343-R cells compared with U343-Con cells. Treatment of U343-R cells with specific inhibitors of JNK or siRNA targeting JNK suppressed up-regulation of invadopodia formation. In addition, paxillin, one of the known JNK effectors which is phosphorylated and affects cell migration, was phosphorylated at serine 178 in JNK activity-dependent manner. Expression of paxillin with mutation of the serine 178 phosphorylation site in U343-R cells blocked invadopodia formation. The present findings suggest that increased formation of invadopodia in U343-R cells is mediated by hyperactivation of JNK-paxillin signaling, and both JNK and paxillin might become targets of novel therapies against TMZ-resistant gliomas.
Keywords	DNA ; antineoplastic agents ; cell movement ; extracellular matrix ; gene expression regulation ; humans ; mitogen-activated protein kinase ; mitogen-activated protein kinase kinase kinase ; mutation ; phosphorylation ; prognosis ; serine ; small interfering RNA
Language	English
Dates of publication	2015-1204
Size	p. 240-247.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2015.10.122
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Article: Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells.

Kimura, Ryuichiro / Ishikawa, Chie / Rokkaku, Takayoshi / Janknecht, Ralf / Mori, Naoki

Biochimica et biophysica acta

2011 Volume 1813, Issue 8, Page(s) 1543–1553

Abstract: ... c-Jun and Fra-1, were phosphorylated, and bound to the AP-1 binding site of the MMP-1 promoter ... in 143B cells. Activated c-Jun and Fra-1 were essential for MMP-1 gene expression in 143B cells ... Mitogen-activated protein kinase pathways including the c-Jun NH(2)-terminal kinase and the extracellular signal-regulated kinase ...

Abstract	Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. Despite the advances in surgical and medical management, the mechanisms underlying human osteosarcoma progression and metastasis remain to be elucidated. Gene expression profiles were compared by the cDNA microarray technique between two different human osteosarcoma sublines, MNNG/HOS and 143B, which differ greatly in spontaneous pulmonary metastatic potential. Here we report an enhanced expression of matrix metalloproteinase (MMP)-1 in the highly metastatic human osteosarcoma cell line 143B. Moreover, the in vitro invasion activity of 143B cells was MMP-1-dependent. The activator protein (AP)-1 binding site in the MMP-1 gene promoter was required for the constitutive expression of MMP-1 in 143B cells. Two AP-1 components, c-Jun and Fra-1, were phosphorylated, and bound to the AP-1 binding site of the MMP-1 promoter in 143B cells. Activated c-Jun and Fra-1 were essential for MMP-1 gene expression in 143B cells. Mitogen-activated protein kinase pathways including the c-Jun NH(2)-terminal kinase and the extracellular signal-regulated kinase activate c-Jun and Fra-1 and thereby regulate c-Jun/Fra-1 mediated events, establishing the mitogen-activated protein kinase/AP-1/MMP-1 axis as important in 143B cells. These data suggest that MMP-1 plays a central role in osteosarcoma invasion. Accordingly, MMP-1 might be a biomarker and therapeutic target for invasive osteosarcomas and pulmonary metastases.
MeSH term(s)	Base Sequence ; Binding Sites/genetics ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Cell Line, Tumor ; DNA Primers/genetics ; Gene Expression Profiling ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors ; JNK Mitogen-Activated Protein Kinases/genetics ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/secondary ; Matrix Metalloproteinase 1/biosynthesis ; Matrix Metalloproteinase 1/genetics ; Models, Biological ; Neoplasm Invasiveness/genetics ; Neoplasm Invasiveness/physiopathology ; Osteosarcoma/genetics ; Osteosarcoma/metabolism ; Osteosarcoma/secondary ; Phosphorylation ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-fos/antagonists & inhibitors ; Proto-Oncogene Proteins c-fos/genetics ; Proto-Oncogene Proteins c-fos/metabolism ; RNA, Small Interfering/genetics ; Transcription Factor AP-1/metabolism
Chemical Substances	DNA Primers ; Proto-Oncogene Proteins c-fos ; RNA, Small Interfering ; Transcription Factor AP-1 ; fos-related antigen 1 ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MMP1 protein, human (EC 3.4.24.7) ; Matrix Metalloproteinase 1 (EC 3.4.24.7)
Language	English
Publishing date	2011-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2011.04.008
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Article: Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis.

Yamagata, Hideo / Matsuzaki, Koichi / Mori, Shigeo / Yoshida, Katsunori / Tahashi, Yoshiya / Furukawa, Fukiko / Sekimoto, Go / Watanabe, Toshihiko / Uemura, Yoshiko / Sakaida, Noriko / Yoshioka, Kazuhiko / Kamiyama, Yasuo / Seki, Toshihito / Okazaki, Kazuichi

Cancer research

2005 Volume 65, Issue 1, Page(s) 157–165

Abstract: ... stage progressed. Activated c-Jun NH(2)-terminal kinase in cancers could directly phosphorylate Smad2/3L ... activity of TGF-beta, was found to decrease, whereas c-Jun NH(2)-terminal kinase tended to induce ...

Abstract	Conversion of normal epithelial cells to tumors is associated with a shift in transforming growth factor-beta (TGF-beta) function: reduction of tumor suppressor activity and increase of oncogenic activity. However, specific mechanisms of this functional alteration during human colorectal carcinogenesis remain to be elucidated. TGF-beta signaling involves Smad2/3 phosphorylated at linker regions (pSmad2/3L) and COOH-terminal regions (pSmad2/3C). Using antibodies specific to each phosphorylation site, we herein showed that Smad2 and Smad3 were phosphorylated at COOH-terminal regions but not at linker regions in normal colorectal epithelial cells and that pSmad2/3C were located predominantly in their nuclei. However, the linker regions of Smad2 and Smad3 were phosphorylated in 31 sporadic colorectal adenocarcinomas. In particular, late-stage invasive and metastatic cancers typically showed a high degree of phosphorylation of Smad2/3L. Their extent of phosphorylation in 11 adenomas was intermediate between those in normal epithelial cells and adenocarcinomas. Whereas pSmad2L remained in the cytoplasm, pSmad3L was located exclusively in the nuclei of Ki-67-immunoreactive adenocarcinomas. In contrast, pSmad3C gradually decreased as the tumor stage progressed. Activated c-Jun NH(2)-terminal kinase in cancers could directly phosphorylate Smad2/3L. Although Mad homology 2 region sequencing in the Smad4 gene revealed a G/A substitution at codon 361 in one adenocarcinoma, the mutation did not correlate with phosphorylation. No mutations in the type II TGF-beta receptor and Smad2 genes were observed in the tumors. In conclusion, pSmad3C, which favors tumor suppressor activity of TGF-beta, was found to decrease, whereas c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence.
MeSH term(s)	Adenocarcinoma/pathology ; Binding Sites ; Cell Transformation, Neoplastic ; Colorectal Neoplasms/pathology ; DNA-Binding Proteins/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Neoplasm Staging ; Phosphorylation ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/physiology ; Smad2 Protein ; Smad3 Protein ; Trans-Activators/metabolism ; Transforming Growth Factor beta/pharmacology
Chemical Substances	DNA-Binding Proteins ; SMAD2 protein, human ; SMAD3 protein, human ; Smad2 Protein ; Smad3 Protein ; Trans-Activators ; Transforming Growth Factor beta ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2005-01-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
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Article: Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells

Kimura, Ryuichiro / Ishikawa, Chie / Rokkaku, Takayoshi / Janknecht, Ralf / Mori, Naoki

Biochimica et biophysica acta. Molecular cell research. 2011 Aug., v. 1813, no. 8

2011

Abstract: ... c-Jun and Fra-1, were phosphorylated, and bound to the AP-1 binding site of the MMP-1 promoter ... in 143B cells. Activated c-Jun and Fra-1 were essential for MMP-1 gene expression in 143B cells ... Mitogen-activated protein kinase pathways including the c-Jun NH₂-terminal kinase and the extracellular signal-regulated kinase ...

Abstract	Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. Despite the advances in surgical and medical management, the mechanisms underlying human osteosarcoma progression and metastasis remain to be elucidated. Gene expression profiles were compared by the cDNA microarray technique between two different human osteosarcoma sublines, MNNG/HOS and 143B, which differ greatly in spontaneous pulmonary metastatic potential. Here we report an enhanced expression of matrix metalloproteinase (MMP)-1 in the highly metastatic human osteosarcoma cell line 143B. Moreover, the in vitro invasion activity of 143B cells was MMP-1-dependent. The activator protein (AP)-1 binding site in the MMP-1 gene promoter was required for the constitutive expression of MMP-1 in 143B cells. Two AP-1 components, c-Jun and Fra-1, were phosphorylated, and bound to the AP-1 binding site of the MMP-1 promoter in 143B cells. Activated c-Jun and Fra-1 were essential for MMP-1 gene expression in 143B cells. Mitogen-activated protein kinase pathways including the c-Jun NH₂-terminal kinase and the extracellular signal-regulated kinase activate c-Jun and Fra-1 and thereby regulate c-Jun/Fra-1 mediated events, establishing the mitogen-activated protein kinase/AP-1/MMP-1 axis as important in 143B cells. These data suggest that MMP-1 plays a central role in osteosarcoma invasion. Accordingly, MMP-1 might be a biomarker and therapeutic target for invasive osteosarcomas and pulmonary metastases.
Keywords	binding sites ; biomarkers ; complementary DNA ; gene expression ; genes ; humans ; interstitial collagenase ; metastasis ; microarray technology ; mitogen-activated protein kinase ; osteosarcoma ; patients
Language	English
Dates of publication	2011-08
Size	p. 1543-1553.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	283444-3
ISSN	0167-4889
ISSN	0167-4889
DOI	10.1016/j.bbamcr.2011.04.008
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Article: Interaction between proliferating cell nuclear antigen and JUN-activation-domain-binding protein 1 in the meristem of rice, Oryza sativa L.

Yamamoto, Taichi / Kimura, Seisuke / Mori, Yoko / Uchiyama, Yukinobu / Ishibashi, Toyotaka / Hashimoto, Junji / Sakaguchi, Kengo

Planta

2003 Volume 217, Issue 2, Page(s) 175–183

Abstract: ... Nipponbare (OsPCNA), we found that OsPCNA interacted in vitro and in vivo with rice JUN-activation-domain ...

Abstract	The eukaryotic polymerase processivity factor, proliferating cell nuclear antigen (PCNA), interacts with many cell cycle-regulator proteins and with proteins involved in the mechanisms of DNA replication and repair. In the present study using two-hybrid analysis with PCNA from rice, Oryza sativa L. cv. Nipponbare (OsPCNA), we found that OsPCNA interacted in vitro and in vivo with rice JUN-activation-domain-binding protein 1 (OsJab1), which is known as COP9/signalsome subunit 5. Both OsPCNA and OsJab1 transcripts were expressed strongly in the shoot apical meristem and weakly in young leaves, flag leaves, ears, roots and root tips. No expression was detected in the mature leaves. The OsPCNA and OsJab1 proteins were expressed and accumulated mostly in the shoot apical meristem and ears, suggesting that OsJab1 is involved in cell proliferation in cooperation with OsPCNA. The role of OsPCNA with OsJab1 in plant DNA proliferation is discussed.
MeSH term(s)	Amino Acid Sequence ; Chromosome Mapping ; Chromosomes, Plant/genetics ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Profiling ; Meristem/metabolism ; Molecular Sequence Data ; Oryza/genetics ; Oryza/metabolism ; Peptide Hydrolases ; Phylogeny ; Plant Leaves/metabolism ; Plant Roots/metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Protein Binding ; RNA, Plant/analysis ; RNA, Plant/genetics ; Sequence Homology, Amino Acid ; Sucrose/metabolism ; Transcription Factors/chemistry ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	DNA-Binding Proteins ; Proliferating Cell Nuclear Antigen ; RNA, Plant ; Transcription Factors ; Sucrose (57-50-1) ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2003-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	208909-9
ISSN	1432-2048 ; 0032-0935 ; 1866-2749
ISSN (online)	1432-2048
ISSN	0032-0935 ; 1866-2749
DOI	10.1007/s00425-003-0981-z
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Article: C-Jun-NH2-terminal kinase mediates expression of connective tissue growth factor induced by transforming growth factor-beta1 in human lung fibroblasts.

Utsugi, Mitsuyoshi / Dobashi, Kunio / Ishizuka, Tamotsu / Masubuchi, Ken / Shimizu, Yasuo / Nakazawa, Tsugio / Mori, Masatomo

American journal of respiratory cell and molecular biology

2003 Volume 28, Issue 6, Page(s) 754–761

Abstract: ... activated c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not ERK in HFL-1 cells. PI3K inhibitors ...

Abstract	Many of the fibrogenic effects of transforming growth factor-beta (TGF-beta) might be mediated by connective tissue growth factor (CTGF). The present study investigates the role of mitogen-activated protein (MAP) kinase in the expression of CTGF mRNA in the human lung fibroblast line, HFL-1. TGF-beta1 enhanced CTGF mRNA levels in a time- and concentration-dependent manner, and this enhancement was also dependent upon transcription. Inhibition of p38 MAP kinase or extracellular signal-regulated kinase (ERK) activation did not affect TGF-beta1-induced CTGF expression. On the other hand, specific inhibitors of phosphatidylinositol 3-kinase (PI3K) suppressed TGF-beta1-induced CTGF expression in a concentration-dependent manner. TGF-beta1 activated c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not ERK in HFL-1 cells. PI3K inhibitors dose-dependently suppressed TGF-beta1-induced JNK, but not p38 MAP kinase activation. Finally, JNK1 and JNK2 antisense oligonucleotides attenuated cellular levels of JNK1 and JNK2 protein, respectively, and repressed TGF-beta1-induced CTGF expression. These results suggest that TGF-beta1-induced CTGF mRNA expression is mediated through the JNK-dependent pathway, whereas p38 MAP kinase and ERK pathways minimally contribute.
MeSH term(s)	Androstadienes/pharmacology ; Anthracenes/pharmacology ; Cells, Cultured ; Chromones/pharmacology ; Connective Tissue Growth Factor ; DNA-Binding Proteins/drug effects ; DNA-Binding Proteins/metabolism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Gene Expression Regulation/drug effects ; Humans ; Imidazoles/pharmacology ; Immediate-Early Proteins/drug effects ; Immediate-Early Proteins/genetics ; Immediate-Early Proteins/metabolism ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; JNK Mitogen-Activated Protein Kinases ; Lung/cytology ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinase 9 ; Mitogen-Activated Protein Kinases/antagonists & inhibitors ; Mitogen-Activated Protein Kinases/drug effects ; Mitogen-Activated Protein Kinases/genetics ; Mitogen-Activated Protein Kinases/metabolism ; Morpholines/pharmacology ; Oligonucleotides, Antisense/pharmacology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Pyridines/pharmacology ; RNA, Messenger/drug effects ; RNA, Messenger/metabolism ; Smad2 Protein ; Trans-Activators/drug effects ; Trans-Activators/metabolism ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/pharmacology ; Transforming Growth Factor beta1 ; Wortmannin ; p38 Mitogen-Activated Protein Kinases
Chemical Substances	Androstadienes ; Anthracenes ; CCN2 protein, human ; Chromones ; DNA-Binding Proteins ; Enzyme Inhibitors ; Imidazoles ; Immediate-Early Proteins ; Intercellular Signaling Peptides and Proteins ; Morpholines ; Oligonucleotides, Antisense ; Pyridines ; RNA, Messenger ; SMAD2 protein, human ; Smad2 Protein ; TGFB1 protein, human ; Trans-Activators ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; Connective Tissue Growth Factor (139568-91-5) ; pyrazolanthrone (1TW30Y2766) ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (31M2U1DVID) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Mitogen-Activated Protein Kinase 9 (EC 2.7.1.24) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 8 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; SB 203580 (OU13V1EYWQ) ; Wortmannin (XVA4O219QW)
Language	English
Publishing date	2003-04-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.4892
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Article: Transforming growth factor-beta and platelet-derived growth factor signal via c-Jun N-terminal kinase-dependent Smad2/3 phosphorylation in rat hepatic stellate cells after acute liver injury.

Yoshida, Katsunori / Matsuzaki, Koichi / Mori, Shigeo / Tahashi, Yoshiya / Yamagata, Hideo / Furukawa, Fukiko / Seki, Toshihito / Nishizawa, Mikio / Fujisawa, Junichi / Okazaki, Kazuichi

The American journal of pathology

2005 Volume 166, Issue 4, Page(s) 1029–1039

Abstract: ... in the nuclei. c-Jun N-terminal kinase (JNK) in the activated HSCs directly phosphorylated Smad2/3 at linker ...

Abstract	After liver injury, transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) regulate the activation of hepatic stellate cells (HSCs) and tissue remodeling. Mechanisms of PDGF signaling in the TGF-beta-triggered cascade are not completely understood. TGF-beta signaling involves phosphorylation of Smad2 and Smad3 at linker and C-terminal regions. Using antibodies to distinguish Smad2/3 phosphorylated at linker regions from those phosphorylated at C-terminal regions, we investigated Smad2/3-mediated signaling in rat liver injured by CCl(4) administration and in cultured HSCs. In acute liver injury, Smad2/3 were transiently phosphorylated at both regions. Although linker-phosphorylated Smad2 remained in the cytoplasm of alpha-smooth muscle actin-immunoreactive mesenchymal cells adjacent to necrotic hepatocytes in centrilobular areas, linker-phosphorylated Smad3 accumulated in the nuclei. c-Jun N-terminal kinase (JNK) in the activated HSCs directly phosphorylated Smad2/3 at linker regions. Co-treatment of primary cultured HSCs with TGF-beta and PDGF activated the JNK pathway, subsequently inducing endogenous linker phosphorylation of Smad2/3. The JNK pathway may be involved in migration of resident HSCs within the space of Disse to the sites of tissue damage because the JNK inhibitor SP600125 inhibited HSC migration induced by TGF-beta and PDGF signals. Moreover, treatment of HSCs with both TGF-beta and PDGF increased transcriptional activity of plasminogen activator inhibitor-1 through linker phosphorylation of Smad3. In conclusion, TGF-beta and PDGF activate HSCs by transmitting their signals through JNK-mediated Smad2/3 phosphorylation at linker regions, both in vivo and in vitro.
MeSH term(s)	Adipocytes/drug effects ; Adipocytes/metabolism ; Animals ; Cells, Cultured ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/drug effects ; DNA-Binding Proteins/metabolism ; Growth Substances/pharmacology ; Immunoblotting ; Immunohistochemistry ; Immunoprecipitation ; JNK Mitogen-Activated Protein Kinases/chemistry ; JNK Mitogen-Activated Protein Kinases/drug effects ; JNK Mitogen-Activated Protein Kinases/metabolism ; Liver/drug effects ; Liver/injuries ; Liver/metabolism ; Male ; Phosphorylation ; Platelet-Derived Growth Factor/pharmacology ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Smad Proteins ; Trans-Activators/chemistry ; Trans-Activators/drug effects ; Trans-Activators/metabolism ; Transforming Growth Factor beta/pharmacology
Chemical Substances	DNA-Binding Proteins ; Growth Substances ; Platelet-Derived Growth Factor ; Smad Proteins ; Trans-Activators ; Transforming Growth Factor beta ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2005-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/s0002-9440(10)62324-3
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Article: Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Rac1-mediated c-Jun NH2-terminal kinase.

Murasawa, S / Matsubara, H / Mori, Y / Masaki, H / Tsutsumi, Y / Shibasaki, Y / Kitabayashi, I / Tanaka, Y / Fujiyama, S / Koyama, Y / Fujiyama, A / Iba, S / Iwasaka, T

The Journal of biological chemistry

2000 Volume 275, Issue 35, Page(s) 26856–26863

Abstract: ... of JNK and c-Jun in cardiac fibroblasts. Ang II markedly stimulated JNK activities, which were abolished ... of c-Jun gene transcription by Ang II was abolished in PKM, DN-Rac1, and DN-MEKK1, in which Ang II-induced ... binding of ATF2/c-Jun heterodimer to the activator protein-1 sequence at -190 played a key role ...

Abstract	Ca(2+)-sensitive tyrosine kinase Pyk2 was shown to be involved in angiotensin (Ang) II-mediated activation of extracellular signal-regulated kinase (ERK) via transactivation of epidermal growth factor receptor (EGF-R). In this study, we tested the involvement of Pyk2 and EGF-R in Ang II-induced activation of JNK and c-Jun in cardiac fibroblasts. Ang II markedly stimulated JNK activities, which were abolished by genistein and intracellular Ca(2+) chelators but partially by protein kinase C depletion. Inhibition of EGF-R did not affect Pyk2 and JNK activation by Ang II. Stable transfection with a dominant negative (DN) mutant for Pyk2 (PKM) completely blocked JNK activation by Ang II. DN mutants of Rac1 (DN-Rac1) and MEK kinase (DN-MEKK1) also abolished it, whereas those of Cdc42, RhoA, and Ha-Ras had no effect. Induction of c-Jun gene transcription by Ang II was abolished in PKM, DN-Rac1, and DN-MEKK1, in which Ang II-induced binding of ATF2/c-Jun heterodimer to the activator protein-1 sequence at -190 played a key role. These results suggest that 1) in cardiac fibroblasts activation of JNK and c-Jun by Ang II is initiated by Pyk2-dependent signalings but not by downstream signals of EGF-R or Ras, 2) Rac1 but not Cdc42 is required for JNK activation by Ang II upstream of MEKK1, and 3) ATF-2/c-Jun binding to the activator protein-1 sequence at -190 plays a key role for induction of c-Jun gene by Ang II.
MeSH term(s)	Angiotensin II/pharmacology ; Animals ; Base Sequence ; Calcium Signaling/drug effects ; Cells, Cultured ; DNA Primers ; Enzyme Activation ; ErbB Receptors/genetics ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; Focal Adhesion Kinase 2 ; Heart Ventricles/cytology ; Heart Ventricles/drug effects ; Heart Ventricles/enzymology ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases/metabolism ; Protein Binding ; Protein Kinase C/metabolism ; Protein-Tyrosine Kinases/metabolism ; Proto-Oncogene Proteins c-jun/metabolism ; Rats ; Rats, Wistar ; Transcriptional Activation ; rac1 GTP-Binding Protein/metabolism ; src-Family Kinases/genetics
Chemical Substances	DNA Primers ; Proto-Oncogene Proteins c-jun ; Angiotensin II (11128-99-7) ; ErbB Receptors (EC 2.7.10.1) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Focal Adhesion Kinase 2 (EC 2.7.10.2) ; Ptk2b protein, rat (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; Protein Kinase C (EC 2.7.11.13) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; rac1 GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2000-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M909999199
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