Depletion of ERK2 but not ERK1 abrogates oncogenic Ras-induced senescence

Shin, Jaehyun; Yang, Jun; Lee, Jang Choon; Baek, Kwan-Hyuck

doi:10.1016/j.cellsig.2013.08.014

Cited by 34 publications

(34 citation statements)

References 59 publications

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“…Moreover, the ratio of pERK2 to pERK1 differs between cultures that are susceptible or resistant to Ras-V12. It increases with senescent phenotype in keeping with data obtained in fibroblasts (Shin et al, 2013). Taken together, these findings show that the consequence of the oncogenic insult also depends on the nature of the founding cell and basal p16 levels are crucial for the final outcome.…”

Section: Waf1supporting

confidence: 78%

“…Of note, in p16-transduced cells the phosphorylated ERK1 isoform was barely detectable and the phosphorylated ERK2 isoform, the key isoform mediating the senescence of murine fibroblasts (Shin et al, 2013), was predominant. Thus, p16 overexpression is able to induce a full senescence suggesting that pRb the pathway was not impaired in these cultures.…”

Section: Ras-v12 Overexpression and Keratinocyte Replicative Senescencementioning

confidence: 99%

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The role of oncogenic Ras in human skin tumorigenesis depends on clonogenic potential of the founding keratinocytes

Maurelli

Tinaburri²,

Gangi³

et al. 2016

Journal of Cell Science

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The role of Ras in human skin tumorigenesis induction is still ambiguous. Overexpression of oncogenic Ras causes premature senescence in cultured human cells and hyperplasia in transgenic mice. Here, we investigated whether the oncogenic insult outcome might depend on the nature of the founding keratinocyte. We demonstrate that overexpression of the constitutively active Ras-V12 induces senescence in primary human keratinocyte cultures, but that some cells escape senescence and proliferate indefinitely. Ras overexpression in transient-amplifying-or stem-cell-enriched cultures shows that p16 (encoded by CDKN2A) levels are crucial for the final result. Indeed, transient-amplifying keratinocytes expressing high levels of p16 are sensitive to Ras-V12-induced senescence, whereas cells with high proliferative potential, but that do not display p16, are resistant. The subpopulation that sustains the indefinite culture growth exhibits stem cell features. Bypass of senescence correlates with inhibition of the pRb (also known as RB1) pathway and resumption of telomerase reverse transcriptase (TERT) activity. Immortalization is also sustained by activation of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) and Akt pathways. Moreover, only transduced cultures originating from cultures bearing stem cells induce tumors in nude mice. Our findings demonstrate that the Ras overexpression outcome depends on the clonogenic potential of the recipient keratinocyte and that only the stem cell compartment is competent to initiate tumorigenesis.

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Section: Waf1supporting

confidence: 78%

Section: Ras-v12 Overexpression and Keratinocyte Replicative Senescencementioning

confidence: 99%

The role of oncogenic Ras in human skin tumorigenesis depends on clonogenic potential of the founding keratinocytes

Maurelli

Tinaburri²,

Gangi³

et al. 2016

Journal of Cell Science

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“…Several studies indicated that oncogenic ras -induced senescence is also mediated by Raf through the MAPK/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinases (ERK) MAPK pathway [7,26,27]. Constitutively active mutants of Raf-1 and MEK1 induce senescence; consistently, inhibition of this pathway by chemical inhibitors of MEK1, dominant negative constructs of MEK1, or shRNA for ERK2 disrupts oncogenic ras -induced senescence.…”

Section: Ois and The P38 Mapk Pathwaymentioning

confidence: 99%

Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence

Xiang

et al. 2014

Trends in Biochemical Sciences

208

157

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Oncogene-induced senescence (OIS) is a tumor-suppressing response that must be disrupted for cancer to develop. Mechanistic insights into OIS have begun to emerge. Activation of the p53/p21WAF1 and/or p16INK4A tumor-suppressor pathways is essential for OIS. Moreover, the DNA damage response, chromatin remodeling and senescence-associated secretory phenotype (SASP) are important for the initiation and maintenance of OIS. This review discusses recent advances in elucidating the mechanisms of OIS, focusing on the roles of the p38 MAPK and PI3K/AKT/mTOR pathways. These studies indicate that OIS is mediated by an intricate signaling network. Further delineation of this network may lead to development of new cancer therapies targeting OIS.

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“…Nevertheless, gene deletion studies in mice have revealed distinct roles of ERK1 and ERK2 in developmental biology, including embryonic stem cell lineage commitment, T cell development, thymocyte maturation, and trophoblast development, with the characterization of ERK2 as being more important (Pagès et al, 1999; Saba-El-Leil et al, 2003; Fischer et al, 2005; Binétruy et al, 2007). In vitro studies of cell lines have also distinguished the role of ERK1 and ERK2 (Bessard et al, 2008; Krens et al, 2008; Lefloch et al, 2008; Shin et al, 2010; Guégan et al, 2013a; Hamilton et al, 2013; Radtke et al, 2013; Shin et al, 2013). …”

Section: The Role Of Raf Mek1/2 and Erk1/2 In Growth Arrest Signmentioning

confidence: 99%

“…For example, in LNCaP, TT, and the glioma line U251 cells, RNA interference of ERK1 or ERK2 had only partial effects whereas simultaneous knockdown of ERK1 and ERK2 was required to effectively inhibit Raf/MEK-induced growth arrest (Hong et al, 2009). In contrast, it was suggested that ERK2, but not ERK1, is necessary for oncogenic Ras-induced senescence based upon the effects of shRNA-mediated depletion of ERK1 and ERK2 in mouse embryonic fibroblasts (Shin et al, 2013). This discrepancy may be due to the differences in cell type-specific expression levels of ERK1 and ERK2.…”

Section: The Role Of Raf Mek1/2 and Erk1/2 In Growth Arrest Signmentioning

confidence: 99%

Growth arrest signaling of the Raf/MEK/ERK pathway in cancer

Park

2014

Front. Biol.

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The Raf/MEK/extracellular signal-regulated kinase (ERK) pathway has a pivotal role in facilitating cell proliferation, and its deregulated activation is a central signature of many epithelial cancers. However paradoxically, sustained activity of Raf/MEK/ERK can also result in growth arrest in many different cell types. This anti-proliferative Raf/MEK/ERK signaling also has physiological significance, as exemplified by its potential as a tumor suppressive mechanism. Therefore, significant questions include in which cell types and by what mechanisms this pathway can mediate such an opposing context of signaling. Particularly, our understating of the role of ERK1 and ERK2, the focal points of pathway signaling, in growth arrest signaling is still limited. This review discusses these aspects of Raf/MEK/ERK-mediated growth arrest signaling.

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Depletion of ERK2 but not ERK1 abrogates oncogenic Ras-induced senescence

Cited by 34 publications

References 59 publications

The role of oncogenic Ras in human skin tumorigenesis depends on clonogenic potential of the founding keratinocytes

The role of oncogenic Ras in human skin tumorigenesis depends on clonogenic potential of the founding keratinocytes

Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence

Growth arrest signaling of the Raf/MEK/ERK pathway in cancer

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