Chapter 1 Ras Signaling and Therapies

Young, Amy; Lyons, Jesse; Miller, Abigail; Phan, Vernon T.; Alarcón, Irma Rangel; McCormick, Frank

doi:10.1016/s0065-230x(09)02001-6

Cited by 187 publications

(152 citation statements)

References 63 publications

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“…Mutant Ras proteins are resistant to downregulation by GAP-mediated hydrolysis of bound GTP and, therefore, signal persistently (1). It has been documented that activating mutations in ras genes are present in 15% of all cancers and perhaps as many as 30% of metastatic human cancers (2).…”

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confidence: 99%

“…It has been documented that activating mutations in ras genes are present in 15% of all cancers and perhaps as many as 30% of metastatic human cancers (2). The mutant Ras proteins typically activate the Raf/MEK/ extracellular signal-regulated kinase (ERK) kinase cascade, which is often associated with the promotion of cell proliferation, and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which functions to suppress apoptosis and contributes to oncogenic transformation (1,3,4).…”

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confidence: 99%

“…The Raf/MEK/ERK kinase cascade represents the predominant and best studied effector pathway downstream of Ras and is critical for Ras-induced oncogenesis (1,4). The Raf proteins, including A-Raf, B-Raf, and C-Raf/Raf-1, are a family of serine/ threonine kinases and can bind to and are activated by GTPbound Ras.…”

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confidence: 99%

“…Raf activation results in activation of the MAPK cascade through phosphorylation of MEK which, in turn, phosphorylates ERK. Following phosphorylation, ERK translocates to the nucleus where it activates various transcription factors or directly phosphorylates 90-kDa ribosomal S6 kinase (RSK), another conserved serine/threonine kinase, which can also translocate to the nucleus and activates transcription through direct phosphorylation (1,19,20). Activation of Raf/MEK/ERK signaling is generally associated with stimulation of cell proliferation, including promoting cell survival by suppression of apoptosis; however, a growing number of studies also suggest that activation of this signaling pathway can promote cell death, including apoptosis (19,(21)(22)(23).…”

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Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

Yue

Zhou

et al. 2012

Journal of Biological Chemistry

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Background:The oncogene Ras induces DR5 expression with undefined mechanism. Results: Both Ras and B-Raf induce DR5 expression through co-activation of ERK and JNK signaling and subsequent cooperative effects among CHOP, Elk1, and c-Jun. Conclusion: Co-activation of ERK and JNK signaling accounts for Ras-induced DR5 expression. Significance: A novel function of DR5 in Ras-or B-Raf-mediated oncogenesis may be suggested.

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confidence: 99%

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confidence: 99%

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Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

Yue

Zhou

et al. 2012

Journal of Biological Chemistry

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“…We used Stat1 +/+ and Stat1 −/− MEFs transformed by Ha-Ras G12V based on studies showing the induction of PI3K signaling by activated Ras and the ability of Stat1 to suppress Ras-mediated tumorigenesis (7,28). We found that Akt S473 phosphorylation as well as phosphorylation of the p70 and p85 isoforms of S6K1 and 2, respectively, were more highly increased in Ras-transformed Stat1 +/+ than Stat1 −/− cells after serum stimulation (Fig.…”

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Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Wang

Patsis

Koromilas

2015

Proc. Natl. Acad. Sci. U.S.A.

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The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27Kip1 and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110γ subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3Kγ signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs.

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Inhibition of Ras Signaling by Blocking Ras–Effector Interactions with Cyclic Peptides

et al. 2015

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Ras genes are frequently activated in human cancers, but the mutant Ras proteins remain largely "undruggable" by the conventional small-molecule approach due to absence of any obvious binding pockets on their surfaces. By screening a combinatorial peptide library followed by structure-activity relationship analysis, we discovered a family of cyclic peptides possessing both Ras-binding and cell-penetrating properties. These cell-permeable cyclic peptides inhibited Ras signaling by binding to Ras-GTP and blocking its interaction with downstream proteins and induced apoptosis of cancer cells. Our results demonstrate the feasibility of developing cyclic

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Chapter 1 Ras Signaling and Therapies

Cited by 187 publications

References 63 publications

Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Inhibition of Ras Signaling by Blocking Ras–Effector Interactions with Cyclic Peptides

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