Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention

Chang, Fumin; Steelman, Linda S.; Lee, J T; Shelton, John G.; Navolanic, Patrick M.; Blalock, William L.; Franklin, Richard A.; McCubrey, James A.

doi:10.1038/sj.leu.2402945

Cited by 630 publications

(513 citation statements)

References 480 publications

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“…Activated MAPK translocates to the nucleus and phosphorylates transcription factors, such as Myc, ELK, and Jun. These transcription factors up-regulate the Cyclin genes, which stimulate the G1 to S phase progression in cell cycle [7,20]. In parallel, Signaling through TORC1-S6K/4EBP also activates Myc to up-regulate the Cyclin genes [21].…”

Section: Ras Activation Stimulates Ras Downstream Effectorsmentioning

confidence: 99%

Ras1CA overexpression in the posterior silk gland improves silk yield

Zhu

et al. 2011

Cell Res

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Sericulture has been greatly advanced by applying hybrid breeding techniques to the domesticated silkworm, Bombyx mori, but has reached a plateau during the last decades. For the first time, we report improved silk yield in a GAL4/UAS transgenic silkworm. Overexpression of the Ras1 CA oncogene specifically in the posterior silk gland improved fibroin production and silk yield by 60%, while increasing food consumption by only 20%. Ras activation by Ras1 CA overexpression in the posterior silk gland enhanced phosphorylation levels of Ras downstream effector proteins, up-regulated fibroin mRNA levels, increased total DNA content, and stimulated endoreplication. Moreover, Ras1 activation increased cell and nuclei sizes, enriched subcellular organelles related to protein synthesis, and stimulated ribosome biogenesis for mRNA translation. We conclude that Ras1 activation increases cell size and protein synthesis in the posterior silk gland, leading to silk yield improvement.

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Section: Ras Activation Stimulates Ras Downstream Effectorsmentioning

confidence: 99%

Ras1CA overexpression in the posterior silk gland improves silk yield

Zhu

et al. 2011

Cell Res

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“…No Erk phosphorylation was detected in CEF transfected with any PI3K isoform and treated with 10 mM UO126. A downstream phosphorylation target of Erk is ribosomal protein S6 kinase, that is, 90 kDa, polypeptide 1 (p90rsk), which after phosphorylation can then activate the transcription factor CREB (Chang et al, 2003). In the presence of UO126 the phosphorylation of p90rsk at serine 380 was abolished, suggesting complete inhibition of both Erk and its downstream targets (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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The catalytic subunits of class I PI3Ks comprise four isoforms: p110a, p110b, p110d and p110c. Cancer-specific gain-of-function mutations in p110a have been identified in various malignancies. Cancer-specific mutations in the non-a isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110b, p110c or p110d is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3b and cause degradation of FoxO1. A functional Erk pathway is required for p110c and p110b transformation but not for transformation by p110d or the H1047R mutant of p110a. Transformation and signaling by p110c and p110b are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110d reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110b and p110c.

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“…They also regulate signal transduction proteins involved in the mitogen-and stress-signaling pathways, such as extracellular signal-regulated kinase, p38 and stress-activated protein kinase. 3 More importantly here is their involvement as mediators of proliferation and malignant transformation. 4 Although most Rho proteins are involved in oncogenesis, invasion and/or metastasis, recent evidence suggests a tumor suppressive role for RhoB (Ras homologous gene B).…”

Section: Introductionmentioning

confidence: 99%