A genome-wide survey of RAS transformation targets

Zuber, Johannes; Tchernitsa, Oleg I.; Hinzmann, Bernd; Schmitz, Anne-Chantal; Grips, Martin; Hellriegel, Martin; Sers, Christine; Rosenthal, André; Schäfer, Reinhold

doi:10.1038/72799

Cited by 265 publications

(212 citation statements)

References 24 publications

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“…Many of the genes whose expression is specifically reduced in heat-shocked Rat1ras cells were found to be stress-associated genes, expanding the findings obtained with S1 analysis of the five selected genes (see selected examples in Table 1). Previous studies performed with ras-transformed rat fibroblasts, grown under optimal conditions, found strong suppression of HSP105 and HSP90 in the transformed cells (Zuber et al, 2000). Interestingly, in Rat1 cells, expression of genes involved in cell cycle control is reduced upon heat shock.…”

Section: Induction Of Stress Genes Is Impaired Inmentioning

confidence: 81%

“…The fact that in yeast Ras is a suppressor of HSPs expression, the sensitivity to stress of transformed cells (Benhar et al, 2001), the reduced levels of some Hsps in ras-transformed cells (Zuber et al, 2000) and Hsf1 inhibition by the Ras/ERK system (Mivechi and Giaccia, 1995;Knauf et al, 1996) suggest that Ha-ras may be a suppressor of HSP70 expression. We tested this notion by transiently expressing Ha-ras val12 in rat fibroblasts and measuring its effect on a HSP70b-Luc reporter gene.…”

Section: Introductionmentioning

confidence: 99%

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Ha-rasval12 induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-rasval12-transformed cells

et al. 2005

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Heat shock proteins (Hsps) are overexpressed in many tumors, but are downregulated in some tumors. To check for a direct effect of Ha-Ras val12 on HSP70 transcription, we transiently expressed the oncoprotein in Rat1 fibroblasts and monitored its effect on HSP70b promoterdriven reporter gene. We show that expression of Ha-Ras val12 induced this promoter. Promoter analysis via systematic deletions and point mutations revealed that Ha-Ras val12 induces HSP70b transcription via heat shock elements (HSEs). Also, Ha-Ras val12 induction of HSEmediated transcription was dramatically reduced in HSF1À/À cells. Yet, residual effect of Ha-Ras val12 that was still measured in HSF1À/À cells suggests that some of the Ha-Ras val12 effect is Hsf1-independent. When HSF1À/À cells, stably expressing Ha-Ras val12 , were grown on soft agar only small colonies were formed suggesting a role for heat shock factor 1 (Hsf1) in Ha-Ras val12 -mediated transformation. Although Ha-ras Val12 seems to be an inducer of HSP70's expression, we found that in Ha-ras Val12-transformed fibroblasts expression of this gene is suppressed. This suppression is correlated with higher sensitivity of Ha-ras val12 -transformed cells to heat shock. We suggest that Ha-ras Val12 is involved in Hsf1 activation, thereby inducing the cellular protective response. Cells that repress this response are perhaps those that acquire the capability to further proliferate and become transformed clones.

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Section: Induction Of Stress Genes Is Impaired Inmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Ha-rasval12 induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-rasval12-transformed cells

et al. 2005

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“…This finding implies that there is an almost complete functional overlap and is at odds with the phenotypic data described earlier [39]. Given the lessons that have been learnt from analysis of oncogenic Ras in promoting tumourigenesis, it would seem to be vital that any comparison of differential Ras isoform signalling is conducted in cells expressing endogenous amounts of each isoform.…”

Section: Introductionmentioning

confidence: 94%

“…Another recent study compared gene expression profiles of mouse and human models of lung cancer bearing endogenous levels of mutated K(B)-Ras to identify a K-Ras gene expression signature in transformed cells [40]. Whilst over-expression studies typically identified approximately 200 genes differentially up-or down-regulated by oncogenic Ras expression, comparative analysis of large human and mouse cancer data sets indicated that fewer that 100 gene targets may represent the endogenous oncogenic K(B)-Ras gene expression signature [38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Omerovic

Laude

Prior

2007

Cell. Mol. Life Sci.

117

122

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Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, KRas4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancers and may suggest new therapeutic approaches.

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“…Elevated FRA-1 levels upon RAS overexpression were observed in a wide variety of tissue cell types. 11,21,[37][38][39] Ha-RASV12 exerted its effect on FRA-1 mainly through the MAPK-ERK pathway, exactly as for vimentin, even though the PI3K pathway could also play a role (Fig. 4d).…”

Section: Fra-1 Inhibition Reduced Vimentin Levels and Cell Migrationmentioning

confidence: 99%

Fra‐1 regulates vimentin during Ha‐RAS‐induced epithelial mesenchymal transition in human colon carcinoma cells

Andreolas

Kalogeropoulou

Voulgari

et al. 2007

Intl Journal of Cancer

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The process of epithelial mesenchymal transition, whereby cells acquire molecular alterations and fibroblastic features, is a fundamental process of embryogenesis and cancer invasion/metastasis. The mechanisms responsible for epithelial mesenchymal transition remain elusive. Human tumors frequently establish constitutively activated RAS signaling, which contributes to the malignant phenotype. In an effort to dissect distinct RAS isoform specific functions, we previously established human colon cell lines stably overexpressing activated Harvey-RAS (Ha-RAS) and Kirsten-RAS (Ki-RAS). Using these, we observed that only oncogenic Ha-RAS overexpression resulted in morphologic and molecular changes suggestive of epithelial to mesenchymal transition. We showed that vimentin, a key molecule of epithelial mesenchymal transition, was differentially regulated between Ha-RAS and Ki-RAS leading to a Ha-RAS specific induction of a migrative phenotype and eventually epithelial to mesenchymal transition. We demonstrated that the AP-1 sites in vimentin promoter could be involved in this regulation. A potential role of FRA-1 was suggested in the regulation of vimentin during the Ha-RAS-induced epithelial to mesenchymal transition, in association with colon cell migration. Our results therefore propose that in colon cells, the induction of epithelial mesenchymal transition by oncogenic Ha-RAS could occur through the overexpression of proteins like FRA-1 and vimentin. ' 2007 Wiley-Liss, Inc.Key words: Ras; vimentin; FRA-1; epithelial-mesenchymal transition RAS proteins (comprising Ha-RAS, Ki-RAS and N-RAS) are very important molecular switches for a wide variety of signal pathways that control proliferation, cell adhesion, apoptosis and cell migration. RAS proteins are often deregulated in cancer, leading to increased invasion and metastasis and decreased apoptosis. Mutations in the RAS family of proto-oncogenes are very common, found in 30% of all human tumors and in 50% of colon tumors in particular. 1 The most common mutations are found on residues 12 and 61. The glycine to valine mutation on residue 12 renders RAS insensitive to inactivation. RAS protein functions within a signal transducing cascade of reactions. Among them, the mitogen activated protein (MAP) kinases that transmit signals downstream to other protein kinases and gene regulatory proteins, are of leading importance. 2 Epithelial to mesenchymal transition (EMT) is a highly conserved and fundamental process that not only governs morphogenesis but also cancer invasion and metastasis in multicellular organisms. There is good evidence that EMT gives rise to the dissemination of single carcinoma cells from the site of primary tumors. In addition, increasing evidence suggests that EMT could play a specific role in the migration of cells from a primary tumor into the blood circulation. EMT can require the cooperation of oncogenic RAS or tyrosine kinase receptor, with endogenous signaling molecules. It involves the transition from an epithelial to a fibroblastic or mesench...

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A genome-wide survey of RAS transformation targets

Cited by 265 publications

References 24 publications

Ha-rasval12 induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-rasval12-transformed cells

Ha-rasval12 induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-rasval12-transformed cells

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Fra‐1 regulates vimentin during Ha‐RAS‐induced epithelial mesenchymal transition in human colon carcinoma cells

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