Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun

Bitomsky, Nadja; Böhm, Maret; Klempnauer, Karl‐Heinz

doi:10.1038/sj.onc.1208064

Cited by 129 publications

(116 citation statements)

References 35 publications

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“…It has been well established that the DNA binding and transactivating activity of Sp transcription factors are largely modulated by posttranslational modifications such as phosphorylation (Su et al, 1999;Yang et al, 2001a, b). Also, an earlier study reported that Pdcd4 blocks phosphorylation of c-Jun, this being achieved either via JNK regulation or direct interaction with c-Jun (Bitomsky et al, 2004). More recently, we have shown that pdcd4 inhibits c-Jun N-terminal phosphorylation by targeting expression of Map4K1 with consequent inhibition of signaling to activate Jun kinase and AP-1 needed for invasion (Yang et al, 2006).…”

Section: Pdcd4 Regulates Invasion and U-par Expressionmentioning

confidence: 75%

“…Pdcd4 has been suggested to be linked to the process of apoptosis in response to different inducers (Shibahara et al, 1995;Zhang and DuBois, 2001), and has been shown to be regulated by topoisomerase inhibitors (Onishi et al, 1998), COX-2 inhibitors (Zhang and DuBois, 2001), Myb (Schlichter et al, 2001) and Akt (Palamarchuk et al, 2005). Molecules regulated by Pdcd4 include p21 (Go¨ke et al, 2004), Cdk4, ornithine decarboxylase (Jansen et al, 2005), carbonic anhydrase II (LankatButtgereit et al, 2004) and JNK/c-Jun/AP-1 (Bitomsky et al, 2004;Yang et al, 2006). Pdcd4 interacts with the translation initiation factors eIF4A and eIF4G and inhibits translation (Yang et al, 2004;Zakowicz et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

et al. 2007

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Section: Pdcd4 Regulates Invasion and U-par Expressionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

et al. 2007

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“…We have previously shown that Pdcd4 inhibits the activity of transcription factors c-Jun and p53 by interfering with their ability to cooperate with p300 (Bitomsky et al, 2004(Bitomsky et al, , 2008. While studying the effect of Pdcd4 on c-Myb, another transcription factor recruiting p300, we noted that Pdcd4 strongly decreased the amount of c-Myb generated from a cytomegalovirus (CMV) promoter-based c-Myb expression vector.…”

Section: C-myb Mrna Is a Translational Target Of Pdcd4mentioning

confidence: 99%

“…Pdcd4 affects transcription of certain genes by modulating the activities of specific transcription factors, such as c-Jun (Yang et al, 2003b;Bitomsky et al, 2004), Sp1 and p53 (Bitomsky et al, 2008). As a translation regulator, Pdcd4 interacts with the eukaryotic translation initiation factor eIF4A, a RNA helicase that catalyzes the unwinding of mRNA secondary structures in 5 0 -untranslated regions (UTRs) (Yang et al, 2003a(Yang et al, , 2004.…”

Section: Introductionmentioning

confidence: 99%

Pdcd4 directly binds the coding region of c-myb mRNA and suppresses its translation

et al. 2011

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Pdcd4 is a novel tumor suppressor protein that functions in the nucleus and the cytoplasm, and appears to be involved in the regulation of transcription and translation. In the cytoplasm, Pdcd4 has been implicated in the suppression of translation of mRNAs containing structured 5 0 -untranslated regions; however, the mechanisms that recruit Pdcd4 to specific target mRNAs and the identities of these mRNAs are mostly unknown. In this study, we have identified c-myb mRNA as the first natural translational target mRNA of Pdcd4. We have found that translational suppression of c-myb mRNA by Pdcd4 is dependent on sequences located within the c-myb-coding region. Furthermore, we have found that the N-terminal domain of Pdcd4 has an important role in targeting Pdcd4 to c-myb RNA by mediating preferential RNA binding to the Pdcd4-responsive region of c-myb mRNA. Overall, our work demonstrates for the first time that Pdcd4 is directly involved in translational suppression of a natural mRNA and provides the first evidence for a key role of the RNA-binding domain in targeting Pdcd4 to a specific mRNA.

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“…The miR-21-mediated downregulation of PDCD4 is required for full induction of AP-1 activity in response to RAS Earlier, it was reported that PDCD4 inhibits the AP-1 activity (Yang et al, 2003b;Wang et al, 2007), likely by interfering with the JNK/c-Jun pathway (Bitomsky et al, 2004;Yang et al, 2006). 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.…”

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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Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun

Cited by 129 publications

References 35 publications

Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

Pdcd4 directly binds the coding region of c-myb mRNA and suppresses its translation

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

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