Transcription of the protein kinase C-δ gene is activated by JNK through c-Jun and ATF2 in response to the anticancer agent doxorubicin

Min, Byung Wook; Kim, Chang Gun; Ko, Jesang; Lim, Yoongho; Lee, Young Han; Shin, Soon Young

doi:10.3858/emm.2008.40.6.699

Cited by 15 publications

(11 citation statements)

References 30 publications

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“…Phosphorylation of JNK in response to overexpression of TMEM67 was significantly inhibited by SP600125 compared to the controls, providing further support for activation of JNK signaling pathway by TMEM67 overexpression. Inhibition of JNK by SP600125 completely cancelled the induction of ATF2 phosphorylation and significantly blocked c-Jun phosphorylation in response to TMEM67 overexpression, consistent with the report that gene transcription can be activated by JNK through c-Jun and ATF2 (Min et al, 2008). …”

Section: Resultssupporting

confidence: 89%

Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK‐dependent pathways

Jin

et al. 2013

Cell Biology International

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TMEM67 mutations are associated with severe autosomal recessive polycystic kidney disease (ARPKD) in both humans and animals. However, the molecular mechanisms underlying the pathogenesis of PKD caused by TMEM67 mutations remain to be determined. We have investigated the possible signaling pathways involved in the pathogenesis of PKD. Overexpression of TMEM67 in human embryonic kidney (HEK293) cells triggered the activation of overall tyrosine phosphorylated proteins, Extracellular Signal-Regulated Kinase (ERK) and c-Jun N-terminal kinase (JNK). Activation was suppressed by pharmacological inhibitors of ERK or JNK. Activation of the mammalian target of rapamycin (mTOR) or p70s kinase (S6K) did not occur, although elevated phosphorylation of eIF4E-binding protein 1 (4E-BP1), a target of S6K, was seen. In animal studies, activation of a variety of signaling molecules was linked to ERK, JNK and 4E-BP1. Significant induction of phosphorylation of tyrosine phosphorylated proteins, ERK and 4E-BP1, at different postnatal ages was detected in mutant kidneys of B6C3Fe a/a-bpck mice, a cystic renal disease mouse model caused by TMEM67 loss of function mutation. Based on these in vitro and in vivo observations, we propose that TMEM67 mutations cause PKD through ERK- and JNK-dependent signaling pathways, which may provide novel insight into the therapy of polycystic kidney diseases.

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Section: Resultssupporting

confidence: 89%

Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK‐dependent pathways

Jin

et al. 2013

Cell Biology International

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“…In salivary epithelial cells, the blockade of PKC α by a dominant-negative PKC α triggered PKC δ-dependent apoptosis, in which ERK was upregulated (Matassa et al 2003). It was shown that in doxorubicin-induced apoptosis, JNK, through activating c-Jun and ATF2 transcription factors, is responsible for an increasing expression of PKC δ gene (Min et al ., 2008). In our experimental setting, Akt appears to take part in the apoptotic process upon the co-suppression of PKC α and β.…”

Section: Discussionmentioning

confidence: 99%

Roles of PKC isoforms in the induction of apoptosis elicited by aberrant Ras

2009

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Emerging evidence indicates that suppression of protein kinase C (PKC) renders the susceptibility of cells expressing mutated ras to apoptosis. Although the effort has been made, the underlying molecular mechanisms are not fully understood. Here, using shRNAs or PKC inhibitor, we demonstrate that the concurrent suppression of PKC α and β induces cells ectopically expressing v-ras to undergo apoptosis. In this apoptotic process, PKC δ is upregulated and translocated from the cytosol to the nucleus. The activated PKC δ associates with and phosphorylates p73 to initiate apoptosis. In this apoptotic process, Akt appears to be downstream of oncogenic Ras. Moreover, overexpression of PKC δ, without co-suppression of PKC α and β, is not apoptotic to the cells, suggesting that PKC δ and α/β function oppositely to facilitate cells harboring v-ras to survive. Thus, our study demonstrates that PKC α and β are necessary for sustaining the homeostasis in cells containing a hyperactive Ras. The abrogation of these two isoforms switches on the p73-regulated apoptotic machinery via the activation of PKC δ.

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“…Such genetic variations are widely encountered in the promoters of a diverse array of genes under the control of AP1 transcription factor (14–36). Our new findings suggest that the genetic variations within the TGACGTCA canonical motif are an important determinant of DNA plasticity and that such conformational flexibility may in turn intimately dictate the affinity of protein-DNA interactions central to gene transcription and regulation.…”

mentioning

confidence: 99%

DNA Plasticity Is a Key Determinant of the Energetics of Binding of Jun-Fos Heterodimeric Transcription Factor to Genetic Variants of TGACGTCA Motif

et al. 2009

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The Jun-Fos heterodimeric transcription factor is a target of a diverse array of signaling cascades that initiate at the cell surface and converge in the nucleus and ultimately result in the expression of genes involved in a multitude of cellular processes central to health and disease. Here, using isothermal titration calorimetry in conjunction with circular dichroism, we report the effect of introducing single nucleotide variations within the TGACGTCA canonical motif on the binding of bZIP domains of Jun-Fos heterodimer to DNA. Our data reveal that the Jun-Fos heterodimer exhibits differential energetics in binding to such genetic variants in the physiologically relevant micromolarsubmicromolar range with the TGACGTCA canonical motif affording the highest affinity. Although binding energetics are largely favored by enthalpic forces and accompanied by entropic penalty, neither the favorable enthalpy nor the unfavorable entropy correlate with overall free energy of binding in agreement with enthalpy-entropy compensation phenomenon widely observed in biological systems. However, a number of variants including the TGACGTCA canonical motif bind to the Jun-Fos heterodimer with high affinity through having overcome such enthalpy-entropy compensation barrier, arguing strongly that better understanding of the underlying invisible forces driving macromolecular interactions may be the key to future drug design. Our data also suggest that the Jun-Fos heterodimer has a preference for binding to TGACGTCA variants with higher AT content, implying that the DNA plasticity may be an important determinant of protein-DNA interactions. This notion is further corroborated by the observation that the introduction of genetic variations within the TGACGTCA motif allows it to sample a much greater conformational space. Taken together, these new findings further our understanding of the role of DNA sequence and conformation on protein-DNA interactions in thermodynamic terms. KeywordsAP1-DNA thermodynamics; Jun-Fos heterodimer; bZIP domain; Single nucleotide variants; DNA plasticity Transcription factors present the terminal link between the transfer of extracellular information in the form of growth factors and cytokines to the site of DNA transcription within the nucleus in a wide variety of cellular processes central to health and disease. This feat is in part executed

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Transcription of the protein kinase C-δ gene is activated by JNK through c-Jun and ATF2 in response to the anticancer agent doxorubicin

Cited by 15 publications

References 30 publications

Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK‐dependent pathways

Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK‐dependent pathways

Roles of PKC isoforms in the induction of apoptosis elicited by aberrant Ras

DNA Plasticity Is a Key Determinant of the Energetics of Binding of Jun-Fos Heterodimeric Transcription Factor to Genetic Variants of TGACGTCA Motif

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