c-Jun promotes cellular survival by suppression of PTEN

Hettinger, Klaudia; Vikhanskaya, Faina; Poh, Mee Kian; Lee, M. K.; Belle, Ian de; Zhang, J.-T.; Reddy, Sujan; Sabapathy, Kanaga

doi:10.1038/sj.cdd.4401946

Cited by 141 publications

(128 citation statements)

References 39 publications

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“…Accordingly, the PTEN and c-Jun levels inversely correlate in a panel of tumor cell lines. Although c-Jun was shown to inhibit the PTEN promoter, the PTEN 5 0 -flanking region targeted by c-Jun was not identified unambiguously (Hettinger et al, 2007;Vasudevan et al, 2007). In our RAS-inducible cell system, transcriptional inhibition does not seem to play a major role in the downregulation of PTEN, as the effect of RAS is entirely relieved by the inhibition of miR-21 (Figure 7c) affecting PTEN at the post-transcriptional level (Meng et al, 2007).…”

Section: Discussionmentioning

confidence: 70%

“…During tumorigenesis, AP-1 regulates a wide variety of target genes, positively controlling cell proliferation, invasion and angiogenesis (Eferl and Wagner, 2003;Ozanne et al, 2007) On the other hand, cell cycle inhibitory and proapoptotic tumor suppressors, such as p16 INK4A and PTEN, are usually repressed by c-Jun/AP-1 (Bakiri et al, 2000;Hettinger et al, 2007;Vasudevan et al, 2007). Although the AP-1-induced promoters are controlled by AP-1 binding to TRE elements, the genes inhibited by AP-1 do not share a common regulatory mechanism, thus suggesting the role of indirect control networks in AP-1-mediated gene repression.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

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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“…Sp1 and c-Jun have also recently been suggested as PTEN transcription factors. 35,36 It is possible that lupeol transcriptionally activates PTEN through these transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation

et al. 2010

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Liver tumor-initiating cells (T-ICs) are capable of self-renewal and tumor initiation and are more chemoresistant to chemotherapeutic drugs. The current therapeutic strategies for targeting stem cell self-renewal pathways therefore represent rational approaches for cancer prevention and treatment. In the present study, we found that Lup-20(29)-en-3b-ol (lupeol), a triterpene found in fruits and vegetables, inhibited the self-renewal ability of liver T-ICs present in both hepatocellular carcinoma (HCC) cell lines and clinical HCC samples, as reflected by hepatosphere formation. Furthermore, lupeol inhibited in vivo tumorigenicity in nude mice and down-regulated CD133 expression, which was previously shown to be a T-IC marker for HCC. In addition, lupeol sensitized HCC cells to chemotherapeutic agents through the phosphatase and tensin homolog (PTEN)-Akt-ABCG2 pathway. PTEN plays a crucial role in the self-renewal and chemoresistance of liver T-ICs; down-regulation of PTEN by a lentiviral-based approach reversed the effect of lupeol on liver T-ICs. Using an in vivo chemoresistant HCC tumor model, lupeol dramatically decreased the tumor volumes of MHCC-LM3 HCC cell line-derived xenografts, and the effect was equivalent to that of combined cisplatin and doxorubicin treatment. Lupeol exerted a synergistic effect without any adverse effects on body weight when combined with chemotherapeutic drugs. Conclusion: Our results suggest that lupeol may be an effective dietary phytochemical that targets liver T-ICs. (HEPATOLOGY 2011;53:160-170)

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“…Wong-Kein Low then proposed that the JNK pathway may play a protective role in radiation-induced cochlear cell damage similar to its role in the CDDP-induced hair cell death. Instead of inducing apoptosis in the latter, JNK promotes DNA repair and maintenance of CDDP-damaged sensory cells (Wang et al, 2004), possibly by down-regulating the expression of PTEN (Hettinger et al, 2007). Currently it is still under debate that the exact role of JNK plays in apoptosis of hair cells.…”

Section: Jnkmentioning

confidence: 99%