Transcription factors control invasion: AP-1 the first among equals

Ozanne, Brad; Spence, Heather J.; McGarry, Lynn; Hennigan, Robert F.

doi:10.1038/sj.onc.1209759

Cited by 241 publications

(237 citation statements)

References 113 publications

(112 reference statements)

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“…As a critical regulator of cell proliferation, apoptosis, tumor invasiveness and angiogenesis, the transcription factor AP-1, mainly formed by dimerization between members of the JUN and FOS protein families, is implicated in multiple hallmarks of cancer (Shaulian and Karin, 2002;Eferl and Wagner, 2003;Ozanne et al, 2007). The tumorigenic role of AP-1, in response to multiple extra-nuclear oncoproteins, has been shown by both dominant-negative inhibitors (Olive et al, 1997;Young et al, 1999) and inactivation of individual AP-1 components.…”

Section: Introductionmentioning

confidence: 99%

“…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: Introductionmentioning

confidence: 99%

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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“…Perturbation of certain signaling modules by, for example, mutations or aberrant growth factor signaling can induce an unfavorable outcome for the organism, such as tumorigenesis and tumor progression (Ozanne et al, 2007). However, many cellular systems are protected by mechanisms that fine-tune the signal transduction pathways by triggering apoptosis in response to aberrant activation of oncogenic pathways and this is felt to be the consequence of an activation of phenotype-specific downstream regulators (Sun et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras–MKK3–p38 to regulate in vitro cellular invasion

et al. 2009

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The Ras oncogene is known to activate three major MAPK pathways, ERK, JNK, p38 and exert distinct cellular phenotypes, that is, apoptosis and invasion through the Ras-MKK3-p38-signaling cascade. We attempted to identify the molecular targets of this pathway that selectively govern the invasive phenotype. Stable transfection of NIH3T3 fibroblasts with MKK3 act cDNA construct revealed similar p38-dependent in vitro characteristics observed in Ha-Ras EJ -transformed NIH3T3 cells, including enhanced invasiveness and anchorage-independent growth correlating with p38 phosphorylation status. To identify the consensus downstream targets of the Ras-MKK3-p38 cascade involved in invasion, in vitro invasion assays were used to isolate highly invasive cells from both, MKK3 and Ha-Ras EJ transgenic cell lines. Subsequently a genome-wide transcriptome analysis was employed to investigate differentially regulated genes in invasive Ha-Ras EJ -and MKK3 act -transfected NIH3T3 fibroblasts. Using this phenotype-assisted approach combined with system level protein-interaction network analysis, we identified FOXM1, PLK1 and CDK1 to be differentially regulated in invasive Ha-Ras EJ -NIH3T3 and MKK3 act -NIH3T3 cells. Finally, a FOXM1 RNAknockdown approach revealed its requirement for both invasion and anchorage-independent growth of Ha-Ras EJand MKK3 act -NIH3T3 cells. Together, we identified FOXM1 as a key downstream target of Ras and MKK3-induced cellular in vitro invasion and anchorage-independent growth signaling.

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“…26 Notably, cathepsin L, which is capable of degrading both basement membrane and extracellular matrix (ECM) proteins, 29 has also been identified as a target of v-Fos/AP-1. 20 In addition, we have found thymosin b4, a major actin sequestering protein, to be important for the regulation of the morphology and migration of Amdc cells. 2 Of the other genes, Ngef is expressed predominantly in brain, and is not much studied overall.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 However, a paucity of data exists on the invasion relevant gene expression changes induced by c-Jun 18 or v-Jun, 19 in comparison with the invasive program induced by v-Fos/AP-1. 20 Our aim was to identify transformation/invasion related genes regulated by c-Jun in the highly invasive Amdc cells. We used a tetracycline-inducible expression system of TAM67 (a dominantnegative mutant of c-Jun lacking the transactivation domain) to inhibit the function of c-Jun, and studied the differences in gene expression using two different microarray platforms.…”

mentioning

confidence: 99%

Identification of integrins α6 and β7 as c‐Jun‐ and transformation‐relevant genes in highly invasive fibrosarcoma cells

Kielosto

Nummela

Järvinen

et al. 2009

Intl Journal of Cancer

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Understanding the mechanisms of tumor cell invasion is essential for our attempts to prevent cancer deaths. We screened by DNA microarrays the c-Jun-and transformation-related gene expression changes in S-adenosylmethionine decarboxylase (AdoMetDC)-overexpressing mouse fibroblasts that are highly invasive in vivo, and their derivatives expressing a tetracycline-inducible dominant-negative mutant of c-Jun (TAM67) or c-Jun shRNA. Among the small set of target genes detected were integrins a6 and b7, cathepsin L and thymosin b4, all upregulated in the AdoMetDC-transformed cells and downregulated upon reversal of transformation by TAM67 or c-Jun shRNA. The upregulation of integrin a6 subunit, pairing with integrin b1, endowed the transformed cells with the capability to attach to basement membrane laminin and to spread. Further, inhibition of integrin a6 or b1 function with neutralizing antibodies blocked the invasiveness of AdoMetDC-transformants and human HT-1080 fibrosarcoma cells in three-dimensional Matrigel. Moreover, immunohistochemical analyses showed strong integrin a6 staining in high-grade human fibrosarcomas. Our data show that c-Jun can regulate all three key steps of invasion: cell adhesion (integrin a6), basement membrane/extracellular matrix degradation (cathepsin L) and cell migration (thymosin b4). In addition, this is the first study to associate integrin b7, known as a leukocyte-specific integrin binding to endothelial/epithelial cell adhesion molecules, with the transformed phenotype in cells of nonleukocyte origin. As tumor cell invasion is a prerequisite for metastasis, the observed critical role of integrin a6b1 in fibrosarcoma cell invasion/spreading allures testing antagonists to integrin a6b1, alone or combined with inhibitors of cathepsin L and thymosin b4, as chemotherapeutic agents. ' 2009 UICC

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Transcription factors control invasion: AP-1 the first among equals

Cited by 241 publications

References 113 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

Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras–MKK3–p38 to regulate in vitro cellular invasion

Identification of integrins α6 and β7 as c‐Jun‐ and transformation‐relevant genes in highly invasive fibrosarcoma cells

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