Analyzing Ras-Associated Cell Proliferation Signaling

Stout, Matthew C.; Asiimwe, Edgar Napoleon; Birkenstamm, James R.; Kim, Su Yeon; Campbell, Paul M.

doi:10.1007/978-1-4939-0888-2_21

Cited by 11 publications

(8 citation statements)

References 42 publications

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“…A Ras-GTP pulldown was performed according to previously established protocols (26,27). Western blot analysis was performed on the pulldown and straight protein lysate samples blotting for K-Ras and K-Ras-GTP (Calbiochem; #OP24), AKT (Cell Signaling; #4691), pAKT (Cell Signaling; #4060), MEK (Cell Signaling; #8727), pMEK (Cell Signaling; #9154) and Vinculin (Sigma; #V9131).…”

Section: Methodsmentioning

confidence: 99%

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

Lal

Cheung

Zarei

et al. 2017

Molecular Cancer Research

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Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer related deaths in the U.S., while colorectal cancer (CRC) is the third most common cancer. The RNA binding protein HuR (ELAVL1), supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and CRC tumor cohorts as compared to normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and CRC (HCT116) cell lines. HuR deficiency has a mild phenotype, in vitro, as HuR-deficient MIA PaCa-2 (MIA.HuR-KO(−/−)) cells had increased apoptosis when compared to isogenic wild-type (MIA.HuR-WT(+/+)) cells. Using this isogenic system, mRNAs were identified that specifically bound to HuR and were required for transforming a 2D culture into 3D (i.e., organoids). Importantly, HuR-deficient MIA PaCa-2 and Hs 766T cells were unable to engraft tumors in vivo compared to control HuR-proficient cells, demonstrating a unique xenograft lethal phenotype. While not as a dramatic phenotype, CRISPR knockout HuR HCT116 colon cancer cells (HCT.HuR-KO(−/−)) showed significantly reduced in vivo tumor growth compared to controls (HCT.HuR-WT(+/+)). Finally, HuR deletion affects KRAS activity and controls a subset of pro-oncogenic genes. Implications The work reported here supports the notion that targeting HuR is a promising therapeutic strategy to treat GI malignancies.

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Section: Methodsmentioning

confidence: 99%

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

Lal

Cheung

Zarei

et al. 2017

Molecular Cancer Research

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“…PI3Ks and their downstream mediators AKT and mTOR constitute the core component of the PI3K/AKT/mTOR signaling pathway which is precisely controlled under normal physiological conditions and is a frequently hyperactivated pathway in cancer [93]. Similar to the MEK-ERK pathway, PI3K is one of the main downstream effectors of Ras dependent signaling and its activation plays dual roles in cell cycle regulation as it can promote cell cycle progression as well as cause cell cycle arrest [94]. Recent studies reveal the involvement of PI3K/AKT/mTOR in the regulation of replicative senescence in human vascular smooth muscle cells [95].…”

Section: Signaling Pathways Involved In Cellular Senescencementioning

confidence: 99%

A prospect of cell immortalization combined with matrix microenvironmental optimization strategy for tissue engineering and regeneration

et al. 2019

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Cellular senescence is a major hurdle for primary cell-based tissue engineering and regenerative medicine. Telomere erosion, oxidative stress, the expression of oncogenes and the loss of tumor suppressor genes all may account for the cellular senescence process with the involvement of various signaling pathways. To establish immortalized cell lines for research and clinical use, strategies have been applied including internal genomic or external matrix microenvironment modification. Considering the potential risks of malignant transformation and tumorigenesis of genetic manipulation, environmental modification methods, especially the decellularized cell-deposited extracellular matrix (dECM)-based preconditioning strategy, appear to be promising for tissue engineering-aimed cell immortalization. Due to few review articles focusing on this topic, this review provides a summary of cell senescence and immortalization and discusses advantages and limitations of tissue engineering and regeneration with the use of immortalized cells as well as a potential rejuvenation strategy through combination with the dECM approach.

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“…Rho and Rac cooperate in the surge of oxidative stress and inflammatory mediators that characterize different pathologic processes [62,63]. Furthermore, Ras is thought to play a central role in the regulation of cellular growth and proliferation [64]. The inhibition of those pathways is associated with a number of protective immunomodulatory effects in inflammatory cells and vascular and myocardial tissue [65,66].…”

Section: Statins Inflammation and Il-1βmentioning

confidence: 99%

IL-1β and Statin Treatment in Patients with Myocardial Infarction and Diabetic Cardiomyopathy

Liberale

Carbone

Camici

et al. 2019

JCM

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Statins are effective lipid-lowering drugs with a good safety profile that have become, over the years, the first-line therapy for patients with dyslipidemia and a real cornerstone of cardiovascular (CV) preventive therapy. Thanks to both cholesterol-related and “pleiotropic” effects, statins have a beneficial impact against CV diseases. In particular, by reducing lipids and inflammation statins, they can influence the pathogenesis of both myocardial infarction and diabetic cardiomyopathy. Among inflammatory mediators involved in these diseases, interleukin (IL)-1β is a pro-inflammatory cytokine that recently been shown to be an effective target in secondary prevention of CV events. Statins are largely prescribed to patients with myocardial infarction and diabetes, but their effects on IL-1β synthesis and release remain to be fully characterized. Of interest, preliminary studies even report IL-1β secretion to rise after treatment with statins, with a potential impact on the inflammatory microenvironment and glycemic control. Here, we will summarize evidence of the role of statins in the prevention and treatment of myocardial infarction and diabetic cardiomyopathy. In accordance with the dual lipid-lowering and anti-inflammatory effect of these drugs and in light of the important results achieved by IL-1β inhibition through canakinumab in CV secondary prevention, we will dissect the current evidence linking statins with IL-1β and outline the possible benefits of a potential double treatment with statins and canakinumab.

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Analyzing Ras-Associated Cell Proliferation Signaling

Cited by 11 publications

References 42 publications

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype

A prospect of cell immortalization combined with matrix microenvironmental optimization strategy for tissue engineering and regeneration

IL-1β and Statin Treatment in Patients with Myocardial Infarction and Diabetic Cardiomyopathy

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