Antisense Oligonucleotides Demonstrate a Dominant Role of c-Ki-RAS Proteins in Regulating the Proliferation of Diploid Human Fibroblasts

Chen, Guan; Oh, Susan; Monia, Brett P.; Stacey, Dennis W.

doi:10.1074/jbc.271.45.28259

Cited by 64 publications

(43 citation statements)

References 32 publications

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“…There are three members of Ras proteins, i.e., H-Ras, K-Ras and N-Ras, and experiments with antisense and knockout studies showed that only K-Ras is required for normal cell growth and/or mouse development (30,31). In human cancer, 85% of these mutations involve K-Ras whereas less than 15% are from HRas (27).…”

Section: Ras Oncogene and The Erk/jnk Mapk Pathwaysmentioning

confidence: 99%

The p38 MAPK stress pathway as a tumor suppressor or more?

Loesch¹

2008

Front Biosci

100

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Abstractp38 mitogen-activated protein kinases (p38 MAPKs) are a group of serine/threonine protein kinases that together with ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinases) MAPKs act to convert different extracellular signals into specific cellular responses through interacting with and phosphorylating downstream targets. In contrast to the mitogenic ERK pathway, mammalian p38 MAPK family proteins (alpha, beta, gamma, and delta), with and without JNK participation, predominantly regulate inflammatory and stress response. Recent emerging evidence suggests that the p38 stress MAPK pathway may function as a tumor suppressor through regulating Ras-dependent and -independent proliferation, transformation, invasion and cell death by isoform-specific mechanisms. A selective activation of a stress pathway to block tumorigenesis may be a novel strategy to control human malignancies. KeywordsThe p38 MAPK pathway; Ras; Tumor Suppressor; isoform-specific; Oncogenesis; Review INTRODUCTIONMAPKs (mitogen-activated protein kinases) consist of ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), and p38 cascades (1, 2). Classically, MAPKs function by phosphorylating substrates containing consensus sequence Ser/Thr-Pro (3) after they are phosphorylated and activated by upstream kinases (MAPK kinases). Each of these MAPK pathways has several family members but all share the same conservative Thr-XaaTyr phosphorylation motif (where Xaa is any amino-acid) (1, 2, 4). The ERK activity is mostly frequently activated by mitogens and required for cell proliferation, differentiation and/or transformation (5, 6). JNK and p38 pathways, on the other hand, are predominantly responsive to stress and cytokine signaling and play an in important role in regulating stress response and inflammation (7,8). MAPKs can be activated almost by all type of stimuli and are consequently involved in many critical biological processes such as proliferation, differentiation, cell death and transformation through regulating downstream gene expression and/or interacting with other signaling cascades.Send correspondence to: Dr. Guan Chen, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, gchen@mcw.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe p38 upstream activators include MAPK kinase 6 (MKK6) and MKK3. Downstream effectors consist of kinases such as MK2 (MAPK-activating protein kinase 2) and PRAK (p38-related/activated protein kinase) as well as transcription factors including ATF-2 (activating transcription factor-2), MEF2 (myocyte enhancement factor 2), and c-Jun (4, 9). The mammalian p38 family consists of four isoform proteins (alpha, beta, gamma, and delta), with p38alpha and p38beta 75% identical in their amino-acid sequence, and p38gamma and p38delta about 60% identical to p38alpha (4, 10). p38alpha and p38beta are susceptible to inhibition by SB drugs (SB203580 and SB202190) wh...

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Section: Ras Oncogene and The Erk/jnk Mapk Pathwaysmentioning

confidence: 99%

The p38 MAPK stress pathway as a tumor suppressor or more?

Loesch¹

2008

Front Biosci

100

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“…Antisense Oligonucleotide Treatment-Treatment of Ki-ras transfectants was essentially as described (34). Cells were seeded at 2 ϫ 10 5 /well in six-well plates.…”

Section: Materials-mentioning

confidence: 99%

“…Cells were seeded at 2 ϫ 10 5 /well in six-well plates. 48 h later, the cells were washed with prewarmed serum-free insulin transferrin/selenious acid-supplemented DMEM and then incubated in this medium with a fixed ratio of oligonucleotide to Lipofectin (2.4 l of Lipofectin/100 M oligonucleotide) for 4 h. The oligonucleotide-containing medium was then replaced with normal growth medium, and growth was continued for 48 h to allow Ras turnover plus reduced Ras mRNA levels to result in reduced Ras protein levels (34).…”

Section: Materials-mentioning

confidence: 99%

Oncogenic Ki-ras Confers a More Aggressive Colon Cancer Phenotype through Modification of Transforming Growth Factor-β Receptor III

Yan

Deng

Friedman

2001

Journal of Biological Chemistry

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“…Mutated K-ras is one of the most frequent genetic events in human cancer, with the highest incidences in pancreatic carcinomas (90%) and colorectal tumors (50%) (3,4). Various strategies have been attempted to selectively inhibit oncogenic Ras activity, including application of farnesyltransferase inhibitors (5,6), antisense technology (7)(8)(9), and small interference RNA (10). Although certain progress has been made in experimental models, therapeutic strategies to selectively inhibit activated ras oncogenes in human cancer remain to be established.…”

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confidence: 99%

p38 MAPK Activation Selectively Induces Cell Death in K-ras-mutated Human Colon Cancer Cells through Regulation of Vitamin D Receptor

Tang

Pramanik

et al. 2004

Journal of Biological Chemistry

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Antisense Oligonucleotides Demonstrate a Dominant Role of c-Ki-RAS Proteins in Regulating the Proliferation of Diploid Human Fibroblasts

Abstract: Although members of the RAS protein family (Ha-, Ki-, and N-RAS) are known to play a key role in normal cell proliferation and to be frequently mutated in naturally occurring tumors, it remains unclear which of these proteins functions to regulate growth in normal cells.

Cited by 64 publications

References 32 publications

The p38 MAPK stress pathway as a tumor suppressor or more?

The p38 MAPK stress pathway as a tumor suppressor or more?

Oncogenic Ki-ras Confers a More Aggressive Colon Cancer Phenotype through Modification of Transforming Growth Factor-β Receptor III

p38 MAPK Activation Selectively Induces Cell Death in K-ras-mutated Human Colon Cancer Cells through Regulation of Vitamin D Receptor

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