C-Jun Activation-Dependent Tumorigenic Transformation Induced Paradoxically by Overexpression or Block of <i>S</i>-Adenosylmethionine Decarboxylase

Paasinen-Sohns, Aino; Kielosto, Mari; Kääriäinen, Essi; Eloranta, Terho O.; Laine, Antti; Jänne, Olli A.; Birrer, Michael J.; Hölttä, Erkki

doi:10.1083/jcb.151.4.801

Cited by 24 publications

(31 citation statements)

References 42 publications

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“…In addition, elevated T␤4 expression has been observed in various malignant cell lines and tumors (15)(16)(17) and its levels seem to be associated with increased tumorigenicity and metastatic potential (10, 13, 18 -20). The increased expression of T␤4 correlates with the invasive capability of the cells, the degree of morphologic transformation, and disintegration of actin filaments (21). Recent studies have also correlated increased T␤4 expression with potentiated cell growth (13,22) but this observation seems not to be universal (2,10).…”

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confidence: 94%

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

Bednarek

Boncela

Smolarczyk

et al. 2008

Journal of Biological Chemistry

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Our data demonstrate that increased intracellular expression of thymosin ␤4 (T␤4) is necessary and sufficient to induce plasminogen activator inhibitor type 1 (PAI-1) gene expression in endothelial cells. To describe the mechanism of this effect, we produced T␤4 mutants with impaired functional motifs and tested their intracellular location and activity. Cytoplasmic distributions of T␤4 (AcSDKPT/4A) , T␤4 (KLKKTET/7A) , and T␤4 (K16A) mutants fused with green fluorescent protein did not differ significantly from those of wild-type T␤4. Overexpression of T␤4, T␤4 (AcSDKPT/4A) , and T␤4 (K16A) affected intracellular formation of actin filaments. As expected, T␤4 (K16A) uptake by nuclei was impaired. On the other hand, overexpression of T␤4 (KLKKTET/7A) resulted in developing the actin filament network typical of adhering cells, indicating that the mutant lacked the actin binding site. The mechanism by which intracellular T␤4 induced the PAI-1 gene did not depend upon the N-terminal tetrapeptide AcSDKP and depended only partially on its ability to bind G-actin or enter the nucleus. Both T␤4 and T␤4 (AcSDKPT/4A) induced the PAI-1 gene to the same extent, whereas mutants T␤4 (KLKKTET/7A) and T␤4 (K16A) retained about 60% of the original activity. By proteomic analysis, the Ku80 subunit of ATPdependent DNA helicase II was found to be associated with T␤4. Ku80 and T␤4 consistently co-immunoprecipitated in a complex from endothelial cells. Co-transfection of endothelial cells with the Ku80 deletion mutants and T␤4 showed that the C-terminal arm domain of Ku80 is directly involved in this interaction. Furthermore, down-regulation of Ku80 by specific short interference RNA resulted in dramatic reduction in PAI-1 expression at the level of both mRNA and protein synthesis. These data suggest that Ku80 functions as a novel receptor for T␤4 and mediates its intracellular activity.2 is the most abundant member of the highly conserved family of acidic polypeptides called ␤-thymosins. Although it is a typical intracellular polypeptide, it plays numerous roles, both intracellularly and extracellularly. Numerous observations indicate that T␤4 is involved in adhesion and spreading of fibroblasts (1, 2), differentiation of endothelial cells (3, 4), directional migration of endothelial cells and keratinocytes (5-8), angiogenesis (3-6, 9, 10), wound healing (6, 7, 11), hair follicle growth (8), and apoptosis (12, 13), and has been described to possess anti-inflammatory properties (11,14). In addition, elevated T␤4 expression has been observed in various malignant cell lines and tumors (15-17) and its levels seem to be associated with increased tumorigenicity and metastatic potential (10, 13, 18 -20). The increased expression of T␤4 correlates with the invasive capability of the cells, the degree of morphologic transformation, and disintegration of actin filaments (21). Recent studies have also correlated increased T␤4 expression with potentiated cell growth (13, 22) but this observation seems not to be universal (2, 10).T␤4 is conside...

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mentioning

confidence: 94%

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

Bednarek

Boncela

Smolarczyk

et al. 2008

Journal of Biological Chemistry

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“…2 Gene annotations have been updated by BLAST searches of nonredundant databases at the National Center for Biotechnology Information. 1 Note that the value for integrin b7 is compressed due to low performance probe set (specific/nonspecific binding) and those for thymosin b4 and cathepsin L due to high signal levels (saturation).…”

Section: Western Blottingmentioning

confidence: 99%

“…NIH3T3 cells stably transfected with the empty pLTRpoly vector (4N) and AdoMetDC cDNA construct (Amdc) 1 were grown in DMEM containing antibiotics, G418, and 5% newborn or fetal bovine serum (FBS; Invitrogen, Carlsbad, CA). An Amdc cell line stably transfected with the tetracycline-inducible expression system of the c-Jun deletion mutant TAM67 (Amdc-pLRT-TAM67) was generated similarly to that previously described for the ODCand ras-transformed cell lines.…”

Section: Cell Culturementioning

confidence: 99%

“…5 Overexpression of AdoMetDC alone induces tumorigenic transformation of rodent fibroblasts. 1 In nude mice, these transformed cells (Amdc) exhibit exceptionally high invasive activity, penetrating rapidly into the peritoneal cavity when inoculated sc into the flanks of the mice. Thus, they provide a valuable tool to study cell invasion.…”

mentioning

confidence: 99%

“…Activation of the proto-oncogene c-jun, a member of the dimeric activator protein 1 (AP-1) transcription factor complex, is required for AdoMetDC-induced transformation. 1 The expression of c-jun is also constitutively increased in many other transformed cell lines 6,7 and human cancers. [8][9][10] Further, a direct jun amplification and overexpression has recently been demonstrated in aggressive human sarcomas.…”

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confidence: 99%

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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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Quantitative assessment of in‐stent dimensions: A comparison of 64 and 16 detector multislice computed tomography to intravascular ultrasound

Beohar¹,

Robbins²,

Cavanaugh³

et al. 2006

Cathet Cardio Intervent

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C-Jun Activation-Dependent Tumorigenic Transformation Induced Paradoxically by Overexpression or Block of S-Adenosylmethionine Decarboxylase

Cited by 24 publications

References 42 publications

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

Ku80 as a Novel Receptor for Thymosin β4 That Mediates Its Intracellular Activity Different from G-actin Sequestering

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

Quantitative assessment of in‐stent dimensions: A comparison of 64 and 16 detector multislice computed tomography to intravascular ultrasound

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