S6K1- and ßTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth

Dorrello, N. Valerio; Peschiaroli, Angelo; Guardavaccaro, Daniele; Colburn, Nancy H.; Sherman, Nicholas E.; Pagano, Michele

doi:10.1126/science.1130276

Cited by 641 publications

(621 citation statements)

References 15 publications

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“…As for PTEN, the RAS-dependent downregulation of PDCD4 is predominantly mediated by miR-21. It has been reported that PDCD4 expression is controlled by ubiquitylation and proteasomal degradation triggered by S6K1-phosphorylation, during cell cycle re-entry (Dorrello et al, 2006). This rapid control mechanism is not implicated in the RAS-dependent downregulation of PDCD4, in which the decrease of PDCD4 parallels the slow induction of miR-21 (Figure 3) and is relieved by the miR-21 knockdown ( Figure 6).…”

Section: Discussionmentioning

confidence: 90%

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: 90%

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

et al. 2008

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“…In vitro ubiquitylation assay was performed using proteins translated in a reticulocyte system, as previously done for SCF βTrcp (Dorrello et al , 2006). Myc‐tagged Fbxl17 (318–701) and Sufu WT or Sufu K257R were in vitro translated using TnT Quick Coupled Transcription/Translation System reticulocyte system from Promega according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

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“…The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been shown to induce the proteolysis of PDCD4 [31] and reduce the transcription of PDCD4 [32]. MicroRNA-21 has been reported to block PDCD4 expression transcriptionally [33] and post-transcriptionally [34].…”

Section: Pdcd4 Increases Timp-2 Expression To Inhibit Breast Cancer Imentioning

confidence: 99%

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

Nieves-Alicea

Colburn

Simeone

et al. 2008

Breast Cancer Res Treat

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High levels of the cyclooxygenase-2 (COX-2) protein have been associated with invasion and metastasis of breast tumors. Both prostaglandin E 2 (PGE 2 ) and interleukin-8 (IL-8) have been shown to mediate the invasive activity of COX-2 in breast cancer cells. Here we expand these studies to determine how COX-2 uses PGE 2 and IL-8 to induce breast cancer cell invasion. We demonstrated that PGE 2 and IL-8 decreased the expression of the tumor suppressor protein Programmed Cell Death 4 (PDCD4). We hypothesized that suppression of PDCD4 expression is vital to the invasive activity of PGE 2 and IL-8. In MCF-7 cells overexpressing PDCD4 (MCF-7/PDCD4), PGE 2 and IL-8 failed to induce invasion, in contrast to the parental MCF-7 cells, thus indicating that PDCD4 blocks breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Silencing TIMP-2 mRNA in MCF-7/PDCD4 cells reversed the anti-invasive effects of PDCD4, allowing PGE 2 and IL-8 to induce the invasion of these cells. Here we report the novel findings that suppression of PDCD4 expression is vital for the invasive activity of COX-2 mediated by PGE 2 and IL-8, and that PDCD4 increases TIMP-2 expression to inhibit breast cancer cell invasion.

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S6K1- and ßTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth

Cited by 641 publications

References 15 publications

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

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

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

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