Promoter Specificity and Biological Activity of Tethered AP-1 Dimers

Bakiri, Latifa; Matsuo, Koichi; Wisniewska, M.; Wagner, Erwin F.; Yaniv, Moshe

doi:10.1128/mcb.22.13.4952-4964.2002

Cited by 172 publications

(161 citation statements)

References 38 publications

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“…As mentioned above, previous studies have shown that other MAPK, such as p38 and ERK1/2, are capable of phosphorylating/activating cJun [35]. While cJun is known to be important for IL-6 production by B cells, other monomeric components of AP-1 are reported to have differential effects on cytokine production that are both cytokine, and potentially celltype specific [35,40,41]. Our data indicate that cFos plays a positive regulatory role in IL-6 production.…”

Section: Discussionsupporting

confidence: 69%

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

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During vaccination or infection, adaptive and innate immune receptors of B cells are engaged by microbial antigens/ligands. A better understanding of how innate and adaptive signaling pathways interact could enlighten B lymphocyte biology as well as aid immunotherapy strategies and vaccine design. To address this goal, we examined the effects of TLR stimulation on BCR and CD40-induced B cell activation. Synergistic production of IL-6 was observed in both human and mouse primary B cells stimulated through B cell antigen receptors, CD40 and TLR7, and these two receptors also cooperated independently of BCR signals. The enhanced IL-6 production was dependent upon the activity of c-Jun kinase (JNK) and cFos. Dual stimulation through CD40 and TLR7 markedly enhanced JNK activity. The increased level of active JNK in dual-stimulated cells was accompanied by an increase in the level of active AP-1 monomers cJun and cFos. The stimulation of B cells through both CD40 and TLR7 therefore enhanced the production of cytokines through increased JNK signaling and AP-1 activity. In addition, the dual stimulation increased cFos/AP-1 species in stimulated cells, effectively expanding the repertoire of AP-1 dimers as compared to singly stimulated B cells. IntroductionNatural immune responses to microbes and responses induced by vaccination involve the cooperation of innate and adaptive immunity. B lymphocytes express receptors that allow them to respond to both antigen-specific and innate immune stimuli [1,2]. One of the key receptors involved in adaptive humoral responses is the TNF receptor superfamily member CD40. The interaction of CD40 on B cells with its ligand CD154, expressed by activated T cells, is integral to immunoglobulin production, isotype switching, and the formation of germinal centers [3], important events in the development of long-lived humoral memory. CD40 stimulation also contributes to B cell antigen presentation by the upregulation of T cell co-stimulatory molecules and production of acute phase cytokines such as . Previous studies have shown that dual stimulation of B cells through the BCR and CD40 leads to an enhancement of Ig and cytokine production [7]. However, the effects and mechanisms of interactions between innate immune receptors and BCR or CD40 expressed by B cells are not yet well defined.B cells can be activated through engagement of a variety of innate immune receptors, including Toll-like receptors (TLR). TLR are related to the Drosophila receptor Toll, important for dorsal-ventral patterning in the developing fly as well as resistance to microbes [8]. The TLR in higher organisms act as sensors of infection or 'danger' by recognizing molecular patterns associated with microbes and/or cellular damage. As natural surveyors of environmental stresses, TLR induce immune cell activity and direct the initial stages of immune responses [9]. Of the 13 TLR mammalian genes [11,12]. TLR7 and -8 bind singlestranded RNA as natural ligands, but also confer responsiveness to guanosine derivatives and the imi...

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Section: Discussionsupporting

confidence: 69%

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

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“…To test the PDCD4 inhibitory activity in FRTL-5/ER-RAS cells, we analysed the tamoxifen induction of a prototype AP-1 reporter, in presence of increasing amounts of the PDCD4 expression vector. We also analysed the PDCD4 inhibitory activity toward the ectopically expressed c-Jun/Fra-1-tethered heterodimer (Bakiri et al, 2002). Cotransfection analysis showed that PDCD4 decreased significantly both the AP-1 activity induced by either the RAS oncoproteins (Figure 7a) or the coexpressed c-Jun/Fra-1 heterodimer (Figure 7b), which represents one of the major RASinduced AP-1 complexes.…”

Section: Identification Of the Ras-responsive Ap-1 Sites Of The Mir-2mentioning

confidence: 99%

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

et al. 2008

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The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1-and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.

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“…24 Although AP-1 members can activate a set of common target genes, different AP-1 dimer compositions produce different biological outcomes, suggesting that they can also selectively regulate distinct sets of genes. 25,26 In addition, some biological effects of AP-1 members are the result of their ability to repress gene expression, such as inhibition of p53 by c-Jun. 27 In this respect, we have investigated the mechanism of DNp73 regulation through the Az pathway with reference to the specificity of AP-1 members in regulating this process.…”

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confidence: 99%

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

et al. 2014

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Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical-and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.

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Promoter Specificity and Biological Activity of Tethered AP-1 Dimers

Cited by 172 publications

References 38 publications

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

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