JNK2: A Negative Regulator of Cellular Proliferation

Sabapathy, Kanaga; Wagner, Erwin F.

doi:10.4161/cc.3.12.1315

Cited by 81 publications

(67 citation statements)

References 22 publications

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“…It is well known that all three JNK isoforms are able to phosphorylate the transcription factor c-Jun and to play distinct biological functions in different systems [15,[19][20][21]24,[34][35][36]. We found that PAR-1 and PAR-2 activations both resulted in JNK1 phosphorylation.…”

Section: Role Of Three Jnk Isoforms In Par-induced Chemokine Gro/cincmentioning

confidence: 52%

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Proteinase-activated receptor-1 and -2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain

Wang

Luo

Reiser

2006

Biochemical Journal

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Activation of both PAR-1 (proteinase-activated receptor-1) and PAR-2 resulted in release of the chemokine GRO (growth-regulated oncogene)/CINC-1 (cytokine-induced neutrophil chemoattractant-1), a functional counterpart of human interleukin-8, from rat astrocytes. Here, we investigate whether the two PAR receptor subtypes can signal separately. PAR-2-induced GRO/CINC-1 release was independent of protein kinase C, phosphoinositide 3-kinase and MEK (mitogen-activated protein kinase kinase)-1/2 activation, whereas these three kinases were involved in PAR-1-induced GRO/CINC-1 release. Despite such clear differences between PAR-1 and PAR-2 signalling pathways, JNK (c-Jun N-terminal kinase) was identified in both signalling pathways to play a pivotal role. By isoform-specific loss-of-function studies using small interfering RNA against JNK1–3, we demonstrate that different JNK isoforms mediated GRO/CINC-1 secretion, when it was induced by either PAR-1 or PAR-2 activation. JNK2 and JNK3 isoforms were both activated by PAR-1 and essential for chemokine GRO/CINC-1 secretion, whereas PAR-1-mediated JNK1 activation was mainly responsible for c-Jun phosphorylation, which was not involved in GRO/CINC-1 release. In contrast, PAR-2-induced JNK1 activation, which failed to phosphorylate c-Jun, uniquely contributed to GRO/CINC-1 release. Therefore our results show for the first time that JNK-mediated chemokine GRO/CINC-1 release occurred in a JNK isoform-dependent fashion and invoked PAR subtype-specific mechanisms. Furthermore, here we demonstrate that activation of PAR-2, as well as PAR-1, rescued astrocytes from ceramide-induced apoptosis via regulating chemokine GRO/CINC-1 release. Taken together, our results suggest that PAR-1 and PAR-2 have overlapping functions, but can activate separate pathways under certain pathological conditions to rescue neural cells from cell death. This provides new functional insights into PAR/JNK signalling and the protective actions of PARs in brain.

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Section: Role Of Three Jnk Isoforms In Par-induced Chemokine Gro/cincmentioning

confidence: 52%

“…These JNKs have two or four sub-isoforms resulting from alternative splicing [13]. It has been shown that JNKs are involved in numerous physiological or pathological processes, including proliferation [14,15], differentiation [16][17][18] and cell death [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Proteinase-activated receptor-1 and -2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain

Wang

Luo

Reiser

2006

Biochemical Journal

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“…A primary dimerization partner for c-JUN is ATF2 (18), and it has been demonstrated that for a number of stimuli, such as adenovirus E1A protein (49), ischemia reperfusion (53), and genotoxic agents (52) tion also requires p-ATF2, which encodes an active histone acetyltransferase. Consequently, we tested for a possible role of p-ATF2 in the induction of the c-JUN gene and in the action of c-JUN on downstream AA-regulated genes.…”

Section: Discussionmentioning

confidence: 99%

“…JNK2 appears to bind to c-Jun with greater affinity and to target it for degradation, whereas JNK1 may be more effective in phosphorylating c-Jun leading to activation and stabilization (17). It has been proposed that the opposing effects of the JNK1 and JNK2 on the cell cycle and cell proliferation may be the consequence of opposite actions on c-Jun (18). However, Jaeschke et al (19) have presented evidence that JNK1 and JNK2 are both positive regulators of c-Jun.…”

mentioning

confidence: 99%

Auto-activation of c-JUN Gene by Amino Acid Deprivation of Hepatocellular Carcinoma Cells Reveals a Novel c-JUN-mediated Signaling Pathway

Balasubramanian

Shan

et al. 2011

Journal of Biological Chemistry

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Limitation of dietary protein/amino acid (AA)2 availability negatively impacts general health in mammals, particularly in pregnancy (1) and early development (2), and can be a contributing factor in the progression of diseases associated with cachexia, such as cancer (3). Conversely, dietary protein limitation is beneficial to some patients with renal disease (4) and a diet deficient in a single essential AA can lead to life span extension (5, 6). Mammalian cells monitor AA levels and respond to AA deprivation by altering the expression of a wide variety of genes (7). The mechanisms by which these events occur are not fully understood, but protein/AA deprivation activates an AA response (AAR) (8, 9), which is a collection of signal transduction pathways, the best studied of which is the general control nonderepressible 2 (GCN2) kinase pathway. The kinase activity of GCN2 is activated by binding uncharged tRNA when there is an increase abundance of any one of the uncharged tRNA molecules. The GCN2 kinase phosphorylates the translation initiation factor eIF2␣ on serine 51, which leads to suppression of general protein synthesis but promotes a paradoxical increase in translation of selected mRNA species, including activating transcription factor 4 (ATF4) (10, 11). ATF4 triggers increased transcription by binding to CCAAT enhancer-binding proteinactivating transcription factor (C/EBP-ATF) sequences that function as AA-response elements (AARE) (8, 9). AA depletion also activates Raf-1 through dephosphorylation by protein phosphatase 2A (12, 13). The enhanced Raf-1 kinase activity triggers the MEK/ERK signaling cascade, which in turn stimulates autophagy in an AA-dependent manner via a G␣-interacting protein (G␣13) (13,14).Similarly, an AA-dependent signaling pathway has been described that involves activation of a G-protein-coupled receptor (G␣12) followed by Rac1-MEKK1-MKK7-JNK2 signaling and ultimately terminates in ATF2 phosphorylation by JNK2 (15). JNK3 is primarily expressed in brain, but both JNK1 and JNK2 are ubiquitous and exhibit broad substrate specificity, as reviewed by Bode and Dong (16). Because knock-out mice for each are viable and show no major deficiencies, they are often considered to have overlapping specificity, but the validity of that assumption remains open for debate. A principal substrate for the JNKs is c-Jun. JNK2 appears to bind to c-Jun with greater affinity and to target it for degradation, whereas JNK1 may be more effective in phosphorylating c-Jun leading to activation and stabilization (17). It has been proposed that the opposing effects of the JNK1 and JNK2 on the cell cycle and cell proliferation may be the consequence of opposite actions on c-Jun (18). However, Jaeschke et al. (19) have presented evidence that JNK1 and JNK2 are both positive regulators of c-Jun. It is clear that the precise functions of the JNKs will require * This work was supported, in whole or in part, by National Institutes of Health Grant DK-092062 (to M. S. K.

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“…25 JNK is induced by various types of cellular stress and JNK activity can result in enhanced proliferation and survival as well as in apoptotic responses. 26,27 Conclusively, genes regulated by JNK or AP1 such as cyclin D1, p53, p16 and p21 28,29 are involved in cell proliferation and apoptosis. An involvement of FHL2 in the MAPK signaling is also demonstrated by the finding that FHL2 can bind directly to ERK2.…”

Section: Introductionmentioning

confidence: 99%

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Martin¹,

Kleiber²,

Wixler³

et al. 2007

Cell Cycle

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© 2 0 0 7 L A N D E S B I O S C I E N C E . D O N O T D I S T R I B U T E .[Cell Cycle 6:14, 1779-1788, 15 ABSTRAcTThe transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types of cancer. Here we analyzed for the first time the molecular function of FHL2 in breast cancer. FHL2 is overexpressed in almost all human mammary carcinoma samples tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Cell cycle analysis revealed an upregulation of endogenous FHL2 towards G 2 /M in MDA-MB 231 cells and an accelerated G 2 /M transition when FHL2 expression was suppressed in these cells. In search for G 2 /M specific target genes regulated by FHL2, we found that expression of the cell cycle inhibitor p21 Cip1/Waf1 (hereafter p21) is dependent on FHL2 in MDA-MB 231 breast cancer cells. Downregulation of FHL2 by shRNA abrogated the cell cycle dependent upregulation of p21 as well as the induction of p21 in response to treatment with the DNA damaging agent doxorubicin. FHL2-dependent p21 expression occurs in a p53-independent manner and p21 expression can be downregulated by specific inhibition of mitogen-activated protein kinases (MAPKs), implicating an involvement of MAPK signaling in this regulation. Analysis of FHL2 contribution to the MAPK signaling identified FHL2 as an important downstream effector of MAPKs in breast cancer cells, capable of transactivating endogenous AP1 target genes as well as AP1 dependent reporter genes. Finally, downregulation of FHL2 reduces the ability of MDA-MB 231 cells to form colonies in soft agar, while FHL2 overexpression enhances colony formation of breast cancer cells. Thus, our findings indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21.

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JNK2: A Negative Regulator of Cellular Proliferation

Cited by 81 publications

References 22 publications

Proteinase-activated receptor-1 and -2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain

Proteinase-activated receptor-1 and -2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain

Auto-activation of c-JUN Gene by Amino Acid Deprivation of Hepatocellular Carcinoma Cells Reveals a Novel c-JUN-mediated Signaling Pathway

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

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