Reactivation of proliferin gene expression is associated with increased angiogenesis in a cell culture model of fibrosarcoma tumor progression

Toft, Daniel J.; Rosenberg, Suzanne B.; Bergers, Gabriele; Volpert, Olga V.; Linzer, Daniel I. H.

doi:10.1073/pnas.231364798

Cited by 73 publications

(68 citation statements)

References 39 publications

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“…Although JunB is classically known to antagonize some biological functions of c-Jun such as cell proliferation, 27 both also share redundancy on certain target genes, which include Egfr and Proliferin. 44,45 On the other hand, FosB has been shown to bind in a complex with c-Jun, which was associated with FasL induction and cell death, indicating that c-Jun/FosB dimer has a pro-apoptotic function. 46 Consistently, our data indicate that similar to c-Jun, expression of JunB and FosB could also induce the suppression of paox, increase the level of Az and lead to the subsequent degradation of DNp73.…”

Section: Discussionmentioning

confidence: 99%

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

et al. 2014

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Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical-and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.

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Section: Discussionmentioning

confidence: 99%

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

et al. 2014

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“…These factors play a role in blood vessel formation and remodeling by affecting endothelial cell proliferation, apoptosis, and migration. However, these two factors have opposite functions as mrp/plf is an inhibitor of angiogenesis, whereas proliferin is a promoter of angiogenesis (23)(24)(25)(26). Hox-3.1 is a gene of the homeobox family that is involved in development regulation.…”

Section: Fig 3 Expression Patterns In Genes Differentially Regulatementioning

confidence: 99%

Differential Gene Expression Induced by Insulin and Insulin-like Growth Factor-II through the Insulin Receptor Isoform A

Pandini

Medico

Conte

et al. 2003

Journal of Biological Chemistry

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The human insulin receptor (IR) exists in two isoforms (IR-A and IR-B). IR-A is a short isoform, generated by the skipping of exon 11, a small exon encoding for 12 amino acid residues at the carboxyl terminus of the IR ␣-subunit. Recently, we found that IR-A is the predominant isoform in fetal tissues and malignant cells and binds with a high affinity not only insulin but also insulin-like growth factor-II (IGF-II). To investigate whether the activation of IR-A by the two ligands differentially activate post-receptor molecular mechanisms, we studied gene expression in response to IR-A activation by either insulin or IGF-II, using microarray technology. To avoid the interfering effect of the IGF-IR, IGF-II binding to the IR-A was studied in IGF-IR-deficient murine fibroblasts (R ؊ cells) transfected with the human IR-A cDNA (R؊ /IR-A cells). Gene expression was studied at 0.5, 3, and 8 h. We found that 214 transcripts were similarly regulated by insulin and IGF-II, whereas 45 genes were differentially transcribed. Eighteen of these differentially regulated genes were responsive to only one of the two ligands (12 to insulin and 6 to IGF-II). Twenty-seven transcripts were regulated by both insulin and IGF-II, but a significant difference between the two ligands was present at least in one time point. Interestingly, IGF-II was a more potent and/or persistent regulator than insulin for these genes. Results were validated by measuring the expression of 12 genes by quantitative real-time reverse transcriptase-PCR. In conclusion, we show that insulin and IGF-II, acting via the same receptor, may differentially affect gene expression in cells. These studies provide a molecular basis for understanding some of the biological differences between the two ligands and may help to clarify the biological role of IR-A in embryonic/fetal growth and the selective biological advantage that malignant cells producing IGF-II may acquire via IR-A overexpression.

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“…It has also been found to potently promote angiogenesis in a progressive mouse fibrosarcoma model. 31 The high mobility group AT-hook 1 protein, a chromatin binding and remodeling protein, has recently found to be a c-Jun target also by others, and to enable anchorage-independent growth of fibroblasts. 32,33 Among the genes showing an opposite behaviour, i.e.…”

Section: Discussionmentioning

confidence: 94%

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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Reactivation of proliferin gene expression is associated with increased angiogenesis in a cell culture model of fibrosarcoma tumor progression

Cited by 73 publications

References 39 publications

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

Differential Gene Expression Induced by Insulin and Insulin-like Growth Factor-II through the Insulin Receptor Isoform A

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

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